Pyrazolopyridine derivative having glp-1 receptor agonist effect

ABSTRACT

The present invention provides a compound having the basic structure shown by Formula (I) in which the indole ring and the pyrazolopyridine structure is bound through a substituent, a salt thereof or a solvate of either the compound or a salt of the compound, as well as a preventative agent or a therapeutic agent for non-insulin-dependent diabetes mellitus (Type 2 diabetes) or obesity containing such compound, salt or solvate as an active ingredient.

TECHNICAL FIELD

The present invention relates to a compound which is a GLP-1 receptoragonist having the same effect as GLP-1, a salt thereof, or a solvate ofeither the compound or a salt of the compound. The present inventionfurther relates to a preventative agent or a therapeutic agent fornon-insulin-dependent diabetes mellitus (Type 2 diabetes) or obesitycomprising such a compound, a salt or a solvate as an active ingredient.

BACKGROUND ART

Glucagon-like peptide-1 (GLP-1) is an incretin secreted from L cells inthe small intestine when nutrients pass through the digestive tract, andit is known that the GLP-1 demonstrates a wide variety of effectsthrough the GLP-1 receptor, such as promotion of glucose dependentinsulin secretion, inhibition of glucagon secretion, delaying of gastricemptying, suppression of feeding. Although GLP-1 analog is alreadycommercialized as a therapeutic agent for diabetes, and seen as one ofthe most effective therapeutic agent for diabetes due to its potenteffect in HbA1c reduction and weight loss, all of them require aninvasive subcutaneous administration. As such, development of a GLP-1receptor agonist that can be non-invasively administered is awaited.Attempts were made, for example, to improve the bioavailability at thetime of oral administration of a GLP-1 analog: Semaglutide by using anabsorbefacient (sodium N-(8-(2-hydroxybenzoyl)amino)caprylate: SNAC)(Patent Document 1) and to develop a low molecular GLP-1 receptoragonist (Patent Documents 2 and 3), but a further improvement isrequired in medicinal properties including activity, metabolic stabilityand bioavailability.

The following two compounds for a chemical library are known as2-[(2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-yl)carbonyl]-1H-indol.

Further, Patent Document 4 describes the following pyrazolopyridinederivative as a compound that is useful in the prevention/therapy ofsleeping sickness, leishmaniasis or the like caused by eukaryote: suchas blastocrithidia (e.g. Trypanosomatidae) parasitizing the patient.

CITATION LIST Patent Literature

-   Patent Document 1: WO 2012/080471-   Patent Document 2: WO 2009/111700-   Patent Document 3: WO 2010/114824-   Patent Document 4: WO 2016/038045

SUMMARY OF INVENTION Technical Problem

The problem to be solved by the present invention is to provide acompound which is a GLP-1 receptor agonist having the same effect asGLP-1 peptide that may be non-invasively administered and has animproved activity, metabolic stability and bioavailability, a saltthereof, or a solvate of either the compound or a salt of the compound,and also to provide a preventative agent or a therapeutic agent fornon-insulin-dependent diabetes mellitus (Type 2 diabetes) or obesitycomprising such a compound, salt or solvate as an active ingredient.

Solution to Problem

The present inventors studied extensively to solve this problem andfound that a compound represented by Formula (I), in which the indolering and the pyrazolopyridine structure are bound to each other througha substituent, has the same effect as GLP-1 peptide as a GLP-1 receptoragonis, and thus completed the present invention.

In other words, the following invention is provided as one aspect of thepresent invention.

[1] A compound represented by Formula (I):

-   -   wherein, X is —N═ or —CR^(a)═; R^(a) is selected from a hydrogen        atom, a halogen atom, and C₁₋₆ alkyl;    -   Y is selected from —C(═O)—, —CHR—, and —S(═O)₂—; R is a hydrogen        atom or C₁₋₆ alkyl;    -   Q¹ is C₆₋₁₀ aryl or 5 to 10 membered heteroaryl, wherein C₆₋₁₀        aryl and 5 to 10 membered heteroaryl are optionally substituted        with one to five substituents independently selected from a        halogen atom, C₁₋₆ alkyl (wherein C₁₋₆ alkyl is optionally        substituted with one or more halogen atoms), and C₁₋₆ alkoxy;    -   Q² is 3 to 12 membered heterocyclyl or 5 to 10 membered        heteroaryl, wherein 3 to 12 membered heterocyclyl and 5 to 10        membered heteroaryl are optionally substituted with one to three        substituents independently selected from a halogen atom, C₁₋₆        alkyl (wherein C₁₋₆ alkyl is optionally substituted with one or        more halogen atoms), C₁₋₆ alkoxy, and —NR^(Qa)R^(Qb), and        further, two C₁₋₆ alkyl groups together with a carbon atom to        which they are attached may form C₃₋₈ carbocyclic ring; and        R^(Qa) and R^(Qb) are independently selected from a hydrogen        atom, C₁₋₆ alkyl, and (C₁₋₆ alkyl)carbonyl;    -   R¹, R² and R³ are each independently selected from a hydrogen        atom and C₁₋₆ alkyl (wherein, C₁₋₆ alkyl is optionally        substituted with one or more substituents independently selected        from a halogen atom, C₁₋₆ alkoxy, and hydroxy);    -   R⁴, R⁵ and R⁶ are independently selected from a hydrogen atom, a        halogen atom, and C₁₋₆ alkyl;    -   R⁷ and R⁸ are independently a hydrogen atom or C₁₋₆ alkyl,        wherein C₁₋₆ alkyl is optionally substituted with one or more        substituents independently selected from a halogen atom and        C₃₋₁₅ cycloalkyl, or R⁷ and R⁸ together with a carbon atom to        which they are attached may form C₃₋₁₅ cycloalkane ring, or        C₃₋₁₅ cycloalkane ring formed by R⁷ and R⁸ together is        optionally substituted with one to three C₁₋₆ alkyl, wherein        C₁₋₆ alkyl is optionally substituted with one or more        substituents independently selected from a halogen atom,        hydroxy, —NR^(7a)R^(7b), C₁₋₆ alkoxy, and 3 to 12 membered        heterocyclyl, and R^(7a) and R^(7b) are independently selected        from a hydrogen atom, C₁₋₆ alkyl, and (C₁₋₆ alkyl)carbonyl;    -   n1 is an integer of 0 to 3; n2 is an integer of 0 to 5;    -   R⁹ is selected from a group represented by Formula (IIa), (IIb),        (IIc), (IId):

—CO₂R^(9f), and —C(═O)—NR^(9g)R^(9h); and R^(9a), R^(9b), R^(9c),R^(9d), and R^(9g) are each independently selected from a hydrogen atom,C₁₋₆ alkyl (wherein C₁₋₆ alkyl is optionally substituted with one ormore substituents independently selected from a halogen atom and C₁₋₆alkoxy), and (C₁₋₆ alkyl)carbonyl, R^(9e) is a hydrogen atom, or C₁₋₆alkyl that is optionally substituted with one or more halogen atoms,R^(9f) is a hydrogen atom or C₁₋₆ alkyl, R^(9h) is a hydrogen atom, C₁₋₆alkyl, (C₁₋₆ alkyl)carbonyl, cyano, or —S(═O)_(n3)—R^(9f); n3 is aninteger of 0 to 2, R⁹ is C₁₋₆ alkyl; Z¹ is selected from a grouprepresented by Formula (IIIa), (IIIb), (IIIc), (IIId), and (IIIe):

wherein R^(za) is selected from a hydrogen atom, C₁₋₆ alkyl, and (C₁₋₆alkyl)carbonyl, R^(zb) and R^(zc) are independently a hydrogen atom orC₁₋₆ alkyl, n4 is an integer of 1 to 3, n5 and n6 are independently aninteger of 0 to 10 (* represents a binding position with apyrazolopyridine structure, ** represents a binding position with Z²);

-   -   Z² is selected from C₁₋₆ alkyl, C₃₋₁₅ cycloalkyl, 3 to 12        membered heterocyclyl, C₆₋₁₀ aryl and 5 to 10 membered        heteroaryl, wherein C₃₋₁₅ cycloalkyl, 3 to 12 membered        heterocyclyl, C₆₋₁₀ aryl, and 5 to 10 membered heteroaryl are        optionally substituted with one to five substituents        independently selected from Group A:        Group A: a) oxo,    -   b) a halogen atom,    -   c) cyano,    -   d) —NR^(zd)R^(ze); wherein R^(zd) and R^(ze) are independently        selected from a hydrogen atom, C₁₋₆ alkyl and (C₁₋₆        alkyl)carbonyl, wherein C₁₋₆ alkyl is optionally substituted        with one or more substituents independently selected from        hydroxy, a halogen atom and C₁₋₆ alkoxy,    -   e) —C(═O)—NR^(zf)R^(zg); wherein R^(zf) and R^(zg) are        independently selected from a hydrogen atom, C₁₋₆ alkyl and        (C₁₋₆ alkyl)carbonyl, wherein C₁₋₆ alkyl is optionally        substituted with one or more substituents independently selected        from hydroxy, a halogen atom and C₁₋₆ alkoxy,    -   f) —S(═O)_(n7)—R^(zh); wherein n7 is an integer of 0 to 2,        R^(zh) is a hydrogen atom or C₁₋₆ alkyl,    -   g) C₁₋₆ alkyl; wherein C₁₋₆ alkyl is optionally substituted with        one or more substituent independently selected from a halogen        atom, hydroxy, —NR^(zi)R^(zj), C₁₋₆ alkoxy, and 3 to 12 membered        heterocyclyl, wherein R^(zi) and R^(zj) are independently a        hydrogen atom or C₁₋₆ alkyl, and wherein 3 to 12 membered        heterocyclyl is optionally substituted with one or more        substituents independently selected from hydroxy, C₁₋₆ alkyl and        3 to 12 membered heterocyclyl,    -   h) C₁₋₆ alkoxy; wherein C₁₋₆ alkoxy is optionally substituted        with one or more substituent independently selected from        hydroxy, a halogen atom, and C₁₋₆ alkoxy,    -   i) 3 to 12 membered heterocyclyl; wherein 3 to 12 membered        heterocyclyl is optionally substituted with one or more        substituents independently selected from C₁₋₆ alkyl and (C₁₋₆        alkyl)carbonyl,    -   j) C₆₋₁₀ aryl; wherein C₆₋₁₀ aryl is optionally substituted with        one or more (C₁₋₆ alkyl)carbonyl, and    -   k) 5 to 10 membered heteroaryl; wherein 5 to 10 membered        heteroaryl is optionally substituted with one or more        substituents independently selected from C₁₋₆ alkyl, C₁₋₆        alkoxy, —NR^(zk)R^(zl), and 3 to 12 membered heterocyclyl,        wherein R^(zk) and R^(zl) are independently selected from a        hydrogen atom, C₁₋₆ alkyl and (C₁₋₆ alkyl)carbonyl, and wherein        3 to 12 membered heterocyclyl is optionally substituted with one        or more substituents independently selected from C₁₋₆ alkyl and        (C₁₋₆ alkyl)carbonyl;        a salt thereof, or a solvate of either the compound or a salt of        the compound.

[2] The compound according to [1], a salt thereof, or a solvate ofeither the compound or a salt of the compound, wherein Q¹ is phenyl orpyridyl, and phenyl or pyridyl is substituted with one to foursubstituents independently selected from a halogen atom and C₁₋₆ alkyl.

[3] The compound according to either [1] or [2], a salt thereof, or asolvate of either the compound or a salt of the compound, wherein R⁷ andR⁸ are both a hydrogen atom; R⁷ and R⁸ are both C₁₋₆ alkyl; R⁷ is ahydrogen atom and R⁸ is C₁₋₆ alkyl; or R⁷ and R⁸ together with a carbonatom to which they are attached form C₃₋₈ cycloalkane ring, wherein C₃₋₈cycloalkane ring that has been formed is optionally substituted with oneto two C₁₋₆ alkyl, and C₁₋₆ alkyl is optionally substituted with one ormore substituents independently selected from hydroxy, C₁₋₆ alkoxy, and3 to 12 membered heterocyclyl.

[4] The compound according to any one of [1] to [3], a salt thereof, ora solvate of either the compound or a salt of the compound, wherein Z²is selected from C₁₋₆ alkyl, C₃₋₁₅ cycloalkyl, 3 to 12 memberedheterocyclyl, C₆₋₁₀ aryl, and 5 to 10 membered heteroaryl, wherein C₃₋₁₅cycloalkyl, 3 to 12 membered heterocyclyl, C₆₋₁₀ aryl, and 5 to 10membered heteroaryl are optionally substituted with one to foursubstituents independently selected from Group B:

Group B: a) oxo,

-   -   b) a halogen atom,    -   c) —NR^(zd1)R^(ze1); wherein R^(zd1) and R^(ze1) are        independently selected from a hydrogen atom, C₁₋₆ alkyl and        (C₁₋₆ alkyl)carbonyl, and C₁₋₆ alkyl is optionally substituted        with one or more C₁₋₆ alkoxy,    -   d) —S(═O)_(n7)—R^(zh1); wherein n7 is an integer of 0 to 2,        R^(zh1) is C₁₋₆ alkyl,    -   e) C₁₋₆ alkyl; wherein C₁₋₆ alkyl is optionally substituted with        one or more substituents independently selected from a halogen        atom, hydroxy, —NR^(zi)R^(zj), C₁₋₆ alkoxy, and 3 to 12 membered        heterocyclyl, wherein R^(zi) and R^(zj) are independently a        hydrogen atom or C₁₋₆ alkyl, and wherein 3 to 12 membered        heterocyclyl is optionally substituted with one or more        substituents independently selected from hydroxy, C₁₋₆ alkyl and        3 to 12 membered heterocyclyl,    -   f) C₁₋₆ alkoxy; wherein C₁₋₆ alkoxy is optionally substituted        with one or more hydroxy,    -   g) 3 to 12 membered heterocyclyl; wherein 3 to 12 membered        heterocyclyl is optionally substituted with one or more (C₁₋₆        alkyl)carbonyl,    -   h) 5 to 10 membered heteroaryl; wherein 5 to 10 membered        heteroaryl is optionally substituted with one or more        substituents independently selected from C₁₋₆ alkyl,        —NR^(zk1)R^(zl1), and R^(zk1) and R^(zl1) are independently        selected from a hydrogen atom and C₁₋₆ alkyl.

[5] The compound according to any one of [1] to [4], a salt thereof, ora solvate of either the compound or a salt of the compound, wherein Y is—C(═O)—.

[6] The compound according to any one of [1] to [5], a salt thereof, ora solvate of either the compound or a salt of the compound, wherein R¹is a hydrogen atom.

[7] The compound according to any one [1] to [6], a salt thereof, or asolvate of either the compound or a salt of the compound, wherein n1 andn2 are both 0.

[8] The compound according to any one of [1] to [7], a salt thereof, ora solvate of either the compound or a salt of the compound, wherein R⁹is represented by Formula (IIb):

[9] The compound according to any one of [1] to [8], a salt thereof, ora solvate of either the compound or a salt of the compound, wherein X is—N═, —CH═, or —CF═.

[10] The compound according to any one of [1] to [9], a salt thereof, ora solvate of either the compound or a salt of the compound, wherein Z¹is represented by Formula (IIIa):

(* represents a binding position with a pyrazolopyridine structure, **represents a binding position with Z²).

[11] A pharmaceutical composition comprising the compound according toany one of [1] to [10], a salt thereof, or a solvate of either thecompound or a salt of the compound as an active ingredient.

[12] A preventive agent or a therapeutic agent for non-insulin-dependentdiabetes mellitus (Type 2 diabetes), hyperglycemia, impaired glucosetolerance, insulin dependent diabetes mellitus (Type 1 diabetes),diabetic complication, obesity, hypertension, hyperlipidemia,arteriosclerosis, coronary heart disease, brain infarction,non-alcoholic steatohepatitis, Parkinson's disease, or dementia, whereinthe preventative agent or the therapeutic agent comprises the compoundaccording to any one of [1] to [10], a salt thereof, or a solvate ofeither the compound or a salt of the compound as an active ingredient.An example of dementia is Alzheimer's disease.

[13] A preventive agent or a therapeutic agent for non-insulin-dependentdiabetes mellitus (Type 2 diabetes) or obesity comprising the compoundaccording to any one of [1] to [10], a salt thereof, or a solvate ofeither the compound or a salt of the compound as an active ingredient.

[14] A method for preventing or treating non-insulin-dependent diabetesmellitus (Type 2 diabetes), hyperglycemia, impaired glucose tolerance,insulin dependent diabetes mellitus (Type 1 diabetes), diabeticcomplication, obesity, hypertension, hyperlipidemia, arteriosclerosis,coronary heart disease, brain infarction, non-alcoholic steatohepatitis,Parkinson's disease, or dementia, which comprises administering aneffective amount of the compound according to any one of [1] to [10], asalt thereof, or a solvate of either the compound or a salt of thecompound to a subject. An example of dementia is Alzheimer's disease.

[15] A method for preventing or treating non-insulin-dependent diabetesmellitus (Type 2 diabetes) or obesity, which comprises administering aneffective amount of the compound according to any one of [1] to [10], asalt thereof, or a solvate of either the compound or a salt of thecompound to a subject.

Advantageous Effects of Invention

The compound, a salt thereof, or a solvate of either the compound or asalt of the compound of the present invention is has an effect similarto GLP-1 peptide as a GLP-1 receptor agonist, and provides a non-peptideagent for preventing or treating non-insulin-dependent diabetes mellitus(Type 2 diabetes) or obesity which is expected to provide a sufficientbioavailability through oral administration.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 shows the result of measurement by X-ray powder diffractometry ofthe crystal of a sodium salt hydrate of Compound 1 obtained in Example163 (Sample 160a). The vertical axis shows the diffraction intensity andthe horizontal axis shows the diffraction angle 2θ (°).

FIG. 2 shows the result of measurement by X-ray powder diffractometry ofthe crystal of a sodium salt hydrate of Compound 1 obtained in Example163 (Sample 160b). The vertical axis shows the diffraction intensity andthe horizontal axis shows the diffraction angle 2θ (°).

FIG. 3 shows the result of measurement by X-ray powder diffractometry ofthe crystal of Example Compound 66 obtained in Example 163 (Sample161a). The vertical axis shows the diffraction intensity and thehorizontal axis shows the diffraction angle 2θ (°).

FIG. 4 shows the result of measurement by X-ray powder diffractometry ofthe crystal of Example Compound 66 obtained in Example 163 (Sample161b). The vertical axis shows the diffraction intensity and thehorizontal axis shows the diffraction angle 2θ (°).

FIG. 5 shows the result of measurement by X-ray powder diffractometry ofthe crystal of a calcium salt hydrate of Example Compound 67 obtained inExample 163 (Sample 162a). The vertical axis shows the diffractionintensity and the horizontal axis shows the diffraction angle 2θ (°).

FIG. 6 shows the result of measurement by X-ray powder diffractometry ofthe crystal of a calcium salt hydrate of Example Compound 67 obtained inExample 163 (Sample 162b). The vertical axis shows the diffractionintensity and the horizontal axis shows the diffraction angle 2θ (°).

FIG. 7 shows the result of thermogravimetry/differential thermalanalysis of the crystal of a sodium salt hydrate of Compound 1 obtainedin Example 164. The horizontal axis shows temperature (° C.), and theright vertical axis shows the weight change (%) of the sample inthermogravimetry. The left vertical axis shows the heat flow observed inthe differential thermal analysis.

FIG. 8 shows the result of thermogravimetry/differential thermalanalysis of the crystal of a calcium salt hydrate of Example Compound 67obtained in Example 164. The horizontal axis shows temperature (° C.),and the right vertical axis shows the weight change (%) of the sample inthermogravimetry. The left vertical axis shows the heat flow observed inthe differential thermal analysis.

FIG. 9 shows the impact of Example Compound 67 and exenatide againstinsulin secretion after intravenous administration of glucose in malecynomolgus monkeys. The area under the curve of insulin is shown by amean value±standard error (n=6). Each pharmaceutical agent wasadministered in a crossover design. * indicates that the value of thegroup shows a statistically significant difference versus that ofvehicle group at P<0.025 and ** indicates that the value of the groupshows a statistically significant difference versus that of vehiclegroup at P<0.005 (Williams test). The concentration of each drug is amean value of the measured plasma concentration of the drug.

FIG. 10 shows the impact of Example Compound 67 and exenatide againstplasma glucose levels after intravenous administration of glucose inmale cynomolgus monkeys. The area under the curve of plasma glucose isshown by a mean value±standard error (n=6). Each pharmaceutical agentwas administered in a crossover design. * indicates that the value ofthe group shows a statistically significant difference versus that ofvehicle group at P<0.025, and ** indicates that the value of the groupshows a statistically significant difference versus that of vehiclegroup at P<0.005 (Williams test). The concentration of each drug is amean value of the measured plasma concentration of drug.

FIG. 11 shows the impact of Example Compound 67 and exenatide againstthe food intake of male cynomolgus monkeys. The food intake is shown bya mean value±standard deviation (n=6). Each pharmaceutical agent wasadministered in a crossover design. * indicates that the value of thegroup shows a statistically significant difference versus that ofvehicle group at P<0.025, and ** indicates that the value of the groupshows a statistically significant difference versus that of vehiclegroup at P<0.005 (Williams test).

FIG. 12 shows the time profile of the plasma concentrations for the drugafter oral administration of this substance to male cynomolgus monkeys.Plasma concentrations are represented by mean values of n=2 for eachdosage.

DESCRIPTION OF EMBODIMENTS

The present invention is further described below without being limitedthereby.

Definition

The term “a halogen atom” in the present invention means a fluorineatom, a chlorine atom, a bromine atom, an iodine atom and the like. Ahalogen atoms that is preferred as a substituent of aryl in the presentinvention (e.g. R^(a) when X in Formula (I) is —CR^(a)═) is a fluorineatom and a chlorine atom. A halogen atoms that is preferred as asubstituent of alkyl in the present invention (e.g. a substituent ofC₁₋₆ alkyl when the C₆₋₁₀ aryl or the 5 to 10 membered heteroaryl of Q¹is substituted with C₁₋₆ alkyl) is a fluorine atom and a chlorine atom.Specific examples of C₁₋₆ alkyl having a halogen atom as a substituentinclude fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl,pentafluoroethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, 2-chloroethyl,heptafluoropropyl, 3,3,3-trifluoropropyl, 2,3-dichloropropyl,1-fluoro-3-bromopropyl, 4-bromobutyl, 3,3,3,4,4-pentafluorobutyl,4,4-dichlorobutyl, 5-iodopentyl, 5,5-difluoropentyl, 6-chlorohexyl, and6,6,6-trifluorohexyl.

The term “C₁₋₆ alkyl” in the present invention is a straight chain orbranched chain alkyl group with 1 to 6 carbons. Examples include methyl,ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl,1-methylpropyl, n-pentyl, isopentyl, 2-methylbutyl, 1,1-dimethylpropyl,1-ethylpropyl, n-hexyl, 4-methylpentyl, and 2-ethylbutyl.

The term “C₁₋₆ alkoxy” in the present invention means a group: C₁₋₆alkyl-O— group, of which C₁₋₆ alkyl is already defined. Examples includemethoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy,t-butoxy, 1-methylpropoxy, n-pentyloxy, isopentyloxy, 2-methylbutoxy,1,1-dimethylpropoxy, 1-ethylpropoxy, n-hexyloxy, 4-methylpentyloxy, and2-ethylbutoxy.

The term “(C₁₋₆ alkyl)carbonyl” in the present invention means a group:(C₁₋₆ alkyl)-C(O)— group, of which C₁₋₆ alkyl is already defined.Examples include methylcarbonyl (acetyl), ethylcarbonyl (propionyl),n-propylcarbonyl, i-propylcarbonyl, n-butylcarbonyl, i-butylcarbonyl,sec-butylcarbonyl, t-butylcarbonyl, 1-methylpropylcarbonyl,n-pentylcarbonyl, isopentylcarbonyl, 2-methylbutylcarbonyl,1,1-dimethylpropylcarbonyl, 1-ethylpropylcarbonyl, n-hexylcarbonyl,4-methylpentylcarbonyl, and 2-ethylbutylcarbonyl.

The term “C₆₋₁₀ aryl” in the present invention means an aromaticcarbocyclic group, and it may contain a non-aromatic portion in additionto the aromatic portion. The ring may be monocyclic, or it may be abicyclic aryl that is condensed with a benzene ring or a monocyclic arylring. Examples include phenyl, 1-naphthyl, 2-naphthyl, azulenyl,isochromanyl, 2,4-dihydro-1H-isoquinolin-3-onyl, and1,3-dihydrobenzimidazol-2-onyl. A preferable example is phenyl.

The term “heteroaryl” in the present invention means an aromatic 5 to 10membered cyclic group that comprise, among atoms constituting a ring,one or more hetero atoms selected from a nitrogen atom, an oxygen atomand a sulfur atom, and it may contain a non-aromatic portion in additionto the aromatic portion. The ring may be monocyclic, or it may be abicyclic heteroaryl that is condensed with a benzene ring or amonocyclic heteroaryl ring. Examples include furyl, thienyl, pyrrolyl,imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isooxazolyl,oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl,pyridazinyl, pyrazinyl, triazinyl, benzofuranyl, benzothienyl,benzothiadiazolyl, benzothiazolyl, benzooxazolyl, benzooxadiazolyl,benzoimidazolyl, indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl,cinnolinyl, quinazolinyl, quinoxalinyl, benzodioxolyl, indolizinyl,imidazopyridyl, benzoisoxazolyl, and benzoisothiazolyl.

The term “heterocyclyl” in the present invention means a non-aromaticcyclic group comprising one or more hetero atoms selected from nitrogen,oxygen and sulfur atoms, and it may be completely saturated or partlyunsaturated. The ring may be a monocyclic ring, a bicyclic ring or aspiro ring of 3 to 12 members, preferably 3 to 10 members. Examplesinclude oxetanyl, azetidinyl, 3,7-dioxa-9-azabicyclo[3.3.1]nonanyl,piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl,tetrahydropyranyl, tetrahydrofuranyl, 2-oxa-6-azaspiro[3.3]heptyl,2-azaspiro[3.3]heptyl, 2,6-diazaspiro[3.3]heptyl,2-thia-6-azaspiro[3.3]heptyl, oxazolidinyl, thiazolidinyl,imidazolidinyl, pyrazolidinyl, thianyl, oxanyl, thioxanyl, indolinyl,isoindolinyl, tetrahydroindolinyl, quinuclidinyl, azepinyl, andtropanyl.

The term “C₃₋₁₅ cycloalkyl” of the present invention means a monovalentgroup derived by removing any single hydrogen atom from a cyclicsaturated aliphatic hydrocarbon having 3 to 15 carbons. Also, the term“C₃₋₈ cycloalkyl” means a cycloalkyl of three to eight carbons. Examplesinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,and cyclooctyl. Also, the term “C₃₋₆ cycloalkyl” means a cycloalkyl of 3to 6 carbons. When two groups together form a C₃₋₁₅ cycloalkane ring,the resulting group is bivalent. Examples include cyclopropane-1,1-diyl,cyclobutane-1,1-diyl, cyclopentane-1,1-diyl, cyclohexane-1,1-diyl,cycloheptane-1,1-diyl, and cyclooctane-1,1-diyl.

When the two groups on two carbon atoms are combined to form a C₃₋₈carbocyclic ring, the resulting ring forms a condensed ring. Examplesinclude ring structures such that the two carbon atoms are linked by—CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂CH₂—, and—CH₂CH₂CH₂CH₂CH₂CH₂—.

In addition, the cycloalkane ring, the carbocyclic ring, the cyclichydrocarbon in the cycloalkyl may be a cross-linked ring. Examples ofcross-linked rings in the C₃₋₁₅ cycloalkyl include bicyclo[1.1.0]butane,bicyclo[3.2.1]octane, bicyclo[5.2.0]nonane, bicyclo[4.3.2]undecane,tricyclo[2.2.1.0^(2,6)]heptane, tricyclo[4.3.1.1^(2,5)]undecane,tricyclo[3.3.1.1^(3,7)]decane (adamantane),tricyclo[3.3.1.1^(3,7)]decane-2-ylidene (2-adamantylidene),pentacyclo[4.2.0.0^(2,5).0^(3,8).0^(4,7)]octane (cubane), and examplesof C₃₋₁₅ cycloalkyl include bicyclo[1.1.0]butyl, bicyclo[3.2.1]octyl,bicyclo[5.2.0]nonyl, bicyclo[4.3.2]undecyl,tricyclo[2.2.1.0^(2,6)]heptyl, tricyclo[4.3.1.1^(2,5)]undecyl,adamantyl, 2-adamantylidenyl, and cubanyl.

The present invention provides a compound represented by Formula (I), asalt thereof, or a solvate of either the compound or a salt of thecompound.

X is —N═ or —CR^(a)═; R^(a) is selected from a hydrogen atom, a halogenatom, and C₁₋₆ alkyl. X is preferably —N═, —CH═, or —CF═, morepreferably —CH═.

Y is selected from —C(═O)—, —CHR—, and —S(═O)₂—; R is a hydrogen atom orC₁₋₆ alkyl.

Q¹ is C₆₋₁₀ aryl or 5 to 10 membered heteroaryl, wherein C₆₋₁₀ aryl and5 to 10 membered heteroaryl are optionally substituted with one to fivesubstituents independently selected from a halogen atom, C₁₋₆ alkyl(wherein C₁₋₆ alkyl is optionally substituted with one or more halogenatoms), and C₁₋₆ alkoxy. Q¹ is preferably phenyl or pyridyl, whereinphenyl or pyridyl is substituted with one to four substituentsindependently selected from a halogen atom and C₁₋₆ alkyl. Morepreferably Q¹ is phenyl substituted with two to three substituentsindependently selected from a halogen atom and C₁₋₆ alkyl.

Q² is 3 to 12 membered heterocyclyl or 5 to 10 membered heteroaryl,wherein 3 to 12 membered heterocyclyl and 5 to 10 membered heteroarylare optionally substituted with one to three substituents independentlyselected from a halogen atom, C₁₋₆ alkyl (wherein C₁₋₆ alkyl isoptionally substituted with one or more halogen atoms), C₁₋₆ alkoxy, and—NR^(Qa)R^(Qb), and two C₁₋₆ alkyl groups together with a carbon atom towhich they are attached may form C₃₋₈ carbocyclic ring; and R^(Qa) andR^(Qb) are independently selected from a hydrogen atom, C₁₋₆ alkyl, and(C₁₋₆ alkyl)carbonyl. Preferably, Q² is i) 6 membered heterocyclyl,wherein 6 membered heterocyclyl is optionally substituted with one ormore C₁₋₆ alkyl, and two C₁₋₆ alkyl groups together with a carbon atomto which they are attached may form C₃₋₈ carbocyclic ring, or ii) 5 to 6membered heteroaryl, wherein 5 to 6 membered heteroaryl is optionallysubstituted with one to three substituents independently selected from ahalogen atom, C₁₋₆ alkyl, C₁₋₆ alkoxy, and —NR^(Qc)R^(Qd), and R^(Qc)and R^(Qd) are independently selected from a hydrogen atom and C₁₋₆alkyl. Preferably, Q² is 5 to 6 membered heterocyclyl or heteroaryl,wherein the 5 to 6 membered heterocyclyl and 5 to 6 membered heteroarylare optionally substituted with one to three C₁₋₆ alkyl.

R¹, R² and R³ are each independently selected from a hydrogen atom andC₁₋₆ alkyl (wherein, C₁₋₆ alkyl is optionally substituted with one ormore substituents independently selected from a halogen atom, C₁₋₆alkoxy, and hydroxy). Preferably, the combination of R¹, R² and R³ isselected from: all hydrogen atoms; Riis a hydrogen atom, R² is ahydrogen atom, and R³ is C₁₋₆ alkyl; and R¹ is a hydrogen atom, R² isC₁₋₆ alkyl, and R³ is C₁₋₆ alkyl.

R⁴, R⁵ and R⁶ are independently selected from a hydrogen atom, a halogenatom, and C₁₋₆ alkyl. It is preferred that R⁴, R⁵ and R⁶ areindependently a hydrogen atom or a fluorine atom. More preferably, thecombination of R⁴, R⁵, and R⁶ are: all hydrogen atoms; or R⁴ is ahydrogen atom, R⁵ is a hydrogen atom, and R⁶ is a fluorine atom.

R⁷ and R⁸ are independently a hydrogen atom or C₁₋₆ alkyl, wherein C₁₋₆alkyl is optionally substituted with one or more substituentsindependently selected from a halogen atom and C₃₋₁₅ cycloalkyl, or R⁷and R⁸ together with a carbon atom to which they are attached may formC₃₋₁₅ cycloalkane ring, wherein C₃₋₁₅ cycloalkane ring formed bycombining R⁷ and R⁸ is optionally substituted with one to three C₁₋₆alkyl, wherein C₁₋₆ alkyl is optionally substituted with one or moresubstituents independently selected from a halogen atom, hydroxy,—NR^(7a)R^(7b), C₁₋₆ alkoxy, and 3 to 12 membered heterocyclyl, andR^(7a) and R^(7b) are independently selected from a hydrogen atom, C₁₋₆alkyl, and (C₁₋₆ alkyl)carbonyl. Preferably R⁷ and R⁸ together with acarbon atom to which they are attached form C₃₋₈ cycloalkane ring,wherein the C₃₋₈ cycloalkyl thus formed is optionally substituted withone or more C₁₋₆ alkyl, wherein C₁₋₆ alkyl is optionally substitutedwith one or more hydroxy. The C₃₋₈ cycloalkyl is preferably C₃₋₆cycloalkyl. A preferable C₃₋₆ cycloalkyl is, for example, cyclopentyl.

n1 is an integer of 0 to 3; n2 is an integer of 0 to 5. n1 and n2 areeach preferably 0 to 2, more preferably 0 to 1, and even more preferably0. Also, the combination of n1 and n2 is preferably 0 and 0, 0 and 1, 0and 2, 1 and 0, 1 and 1, 2 and 0, more preferably 0 and 0, 0 and 1, 1and 0, 2 and 0, and even more preferably 0 and 0.

R⁹ is selected from a group represented by Formula (IIa), (IIb), (IIc),(IId):

—CO₂R^(9f), and —C(═O)—NR^(9g)R^(9h); and R^(9a), R^(9b), R^(9c),R^(9d), and R^(9g) are each independently selected from a hydrogen atom,C₁₋₆ alkyl (wherein C₁₋₆ alkyl is optionally substituted with one ormore substituents independently selected from a halogen atom and C₁₋₆alkoxy), and (C₁₋₆ alkyl)carbonyl, R^(9e) is a hydrogen atom, or C₁₋₆alkyl that is optionally substituted with one or more substituentsindependently selected from a halogen atom, R^(9f) is a hydrogen atom orC₁₋₆ alkyl, R^(9h) is a hydrogen atom, C₁₋₆ alkyl, (C₁₋₆ alkyl)carbonyl,cyano, or —S(═O)_(n3)—R^(9i); n3 is an integer of 0 to 2, and R^(9i) isC₁₋₆ alkyl.

Z¹ is selected from a group represented by Formula (IIIa), (IIIb),(IIIc), (IIId), and (IIIe).

wherein R^(za) is selected from a hydrogen atom, C₁₋₆ alkyl, and (C₁₋₆alkyl)carbonyl, R^(zb) and R^(zc) are independently a hydrogen atom orC₁₋₆ alkyl, n4 is an integer of 1 to 3, n5 and n6 are independently aninteger of 0 to 10.

* represents a binding position with a pyrazolopyridine structure, **represents a binding position with Z².

Z² is selected from C₁₋₆ alkyl, C₃₋₁₅ cycloalkyl, 3 to 12 memberedheterocyclyl, C₆₋₁₀ aryl and 5 to 10 membered heteroaryl, wherein C₃₋₁₅cycloalkyl, 3 to 12 membered heterocyclyl, C₆₋₁₀ aryl, and 5 to 10membered heteroaryl are optionally substituted with one to fivesubstituents independently selected from Group A.

Group A: a) oxo,

-   -   b) a halogen atom,    -   c) cyano,    -   d) —NR^(zd)R^(ze); wherein R^(zd) and R^(ze) are independently        selected from a hydrogen atom, C₁₋₆ alkyl and (C₁₋₆        alkyl)carbonyl, wherein C₁₋₆ alkyl is optionally substituted        with one or more substituents independently selected from        hydroxy, a halogen atom and C₁₋₆ alkoxy,    -   e) —C(═O)—NR^(f)R^(zg); wherein R^(zE) and R^(zg) are        independently selected from a hydrogen atom, C₁₋₆ alkyl and        (C₁₋₆ alkyl)carbonyl, wherein C₁₋₆ alkyl is optionally        substituted with one or more substituents independently selected        from hydroxy, a halogen atom and C₁₋₆ alkoxy,    -   f) —S(═O)_(n7)—R^(zh); wherein n7 is an integer of 0 to 2,        R^(zh) is a hydrogen atom or C₁₋₆ alkyl,    -   g) C₁₋₆ alkyl; wherein C₁₋₆ alkyl is optionally substituted with        one or more substituents independently selected from a halogen        atom, hydroxy, —NR^(zi)R^(zj), C₁₋₆ alkoxy, and 3 to 12 membered        heterocyclyl, wherein R^(zi) and R^(zj) are independently a        hydrogen atom or C₁₋₆ alkyl, and wherein 3 to 12 membered        heterocyclyl is optionally substituted with one or more        substituents independently selected from hydroxy, C₁₋₆ alkyl and        3 to 12 membered heterocyclyl,    -   h) C₁₋₆ alkoxy; wherein C₁₋₆ alkoxy is optionally substituted        with one or more substituents independently selected from        hydroxy, a halogen atom, and C₁₋₆ alkoxy,    -   i) 3 to 12 membered heterocyclyl; wherein 3 to 12 membered        heterocyclyl is optionally substituted with one or more        substituents independently selected from C₁₋₆ alkyl and (C₁₋₆        alkyl)carbonyl,    -   j) C₆₋₁₀ aryl; wherein C₆₋₁₀ aryl is optionally substituted with        one or more (C₁₋₆ alkyl)carbonyl, and    -   k) 5 to 10 membered heteroaryl; wherein 5 to 10 membered        heteroaryl is optionally substituted with one or more        substituents independently selected from C₁₋₆ alkyl, C₁₋₆        alkoxy, —NR^(zk)R^(zl), and 3 to 12 membered heterocyclyl,        wherein R^(zk) and R^(zl) are independently selected from a        hydrogen atom, C₁₋₆ alkyl and (C₁₋₆ alkyl)carbonyl, and wherein        3 to 12 membered heterocyclyl is optionally substituted with one        or more substituents independently selected from C₁₋₆ alkyl and        (C₁₋₆ alkyl)carbonyl.

When the C₁₋₆ alkyl in R^(zd), R^(ze), R^(zf) and R^(zg) is substitutedwith hydroxy, C₁₋₆ alkyl is preferably C₂₋₆ alkyl, and more preferablyC₂₋₄ alkyl.

When the C₁₋₆ alkoxy is substituted with hydroxy, C₁₋₆ alkyl ispreferably C₂₋₆ alkyl, and more preferably C₂₋₄ alkyl.

Preferably, Z² is selected from i) C₃₋₁₅ cycloalkyl that is optionallysubstituted with one or more —NR^(zd)R^(ze) ii) C₆₋₁₀ aryl that isoptionally substituted with one to three substituents independentlyselected from Group C, and iii) 5 to 10 membered heteroaryl that isoptionally substituted with one to three substituents independentlyselected from Group D.

More preferably, Z² is selected from i) C₆₋₁₀ aryl that is optionallysubstituted with one to three substituents independently selected fromGroup C, and ii) 5 to 10 membered heteroaryl that is optionallysubstituted with one to three substituents independently selected fromGroup D.

Group C: a) a halogen atom,

-   -   b) —NR^(zd2)R^(ze2); wherein R^(zd2) and R^(ze2) are        independently selected from a hydrogen atom, C₁₋₆ alkyl and        (C₁₋₆ alkyl)carbonyl, wherein C₁₋₆ alkyl is optionally        substituted with one or more C₁₋₆ alkoxy,    -   c) —S(═O)_(n7)—R^(zh1); wherein n7 is an integer of 0 to 2,        R^(zh1) is C₁₋₆ alkyl,    -   d) C₁₋₆ alkyl;    -   e) C₁₋₆ alkoxy; wherein C₁₋₆ alkoxy is optionally substituted        with one or more hydroxy,    -   f) 5 to 10 membered heteroaryl; wherein 5 to 10 membered        heteroaryl is optionally substituted with one or more        substituents independently selected from —NR^(zk1)R^(zl1),        wherein R^(zk1) and R^(zl1) are independently selected from a        hydrogen atom and C₁₋₆ alkyl.

Group D: a) oxo,

-   -   b) a halogen atom,    -   c) C₁₋₆ alkyl; wherein C₁₋₆ alkyl is optionally substituted with        one or more substituents independently selected from a halogen        atom, hydroxy, C₁₋₆ alkoxy, and 3 to 12 membered heterocyclyl,        wherein 3 to 12 membered heterocyclyl is optionally substituted        with one or more C₁₋₆ alkyl, and    -   d) 3 to 12 membered heterocyclyl.

The compound represented by Formula (I) of the present invention ispreferably such that Z¹ is a group represented by Formula (IIIa), Y is—C(═O)—, R⁹ is a group represented by Formula (IIb), R^(9b) is ahydrogen atom, R⁷ and R⁸ together with a carbon atom to which they areattached form C₃₋₁₅ cycloalkane ring that is substituted with one tothree C₁₋₆ alkyl, and the one to three C₁₋₆ alkyl is unsubstituted.

Next, examples of the production method of a compound represented byFormula (I), a salt thereof, or a solvate of either the compound or asalt of the compound are explained by the following schemes.

The compound represented by Formula (I), a salt thereof, or a solvate ofeither the compound or a salt of the compound are produced by conductingi) General production method A1 or General production method A2, ii)General production method B, and iii) General production method C. Thisproduction method is one example of a preferable production method of acompound of Formula (I), in which Z¹ is a group represented by Formula(IIIa), Y is represented by —C(═O)—, R⁹ is a group represented byFormula (IIb), and R^(9b) is a hydrogen atom, that is, a compoundrepresented by Formula (Ia).

It is also an example of a preferable production method for a compoundin which R⁷ and R⁸ together with a carbon atom to which they areattached form a C₃₋₁₅ cycloalkane ring substituted with 1 to 3 C₁₋₆alkyl groups, wherein the alkyl groups are not substituted.

Note that in a case in which a starting material or a target product ofa given step undergoes an undesirable chemical transformation under thereaction condition of that step, it is possible to obtain the targetproduct of that step by protecting or deprotecting a functional group.T. W. Greene, P. G. M. Wuts, Protective Groups in Organic Synthesis,Fourth Edition, John Wiley & Sons, Inc., New York (2007) may be referredto in order to select the protecting group and the method of protectionand deprotection. Some examples of the protection and deprotection of afunctional group are shown in the scheme below.

<General Production Method A1>

Compound f may be synthesized by the General production method A1illustrated by the following scheme.

wherein P² is a hydrogen atom or C₁₋₆ alkyl, Pa is a protective group ofamino, Pa and P^(3b) are independently C₁₋₆ alkyl, or P^(3a) and P^(3b)together with oxygen atoms to which they are attached and a carbon atomto which the oxygen atoms are attached may form 5 to 7 membered1,3-dioxacycloalkane ring, Y¹ is cyano or —CO—OP², Y² is ═O or NH, andX¹ is a leaving group.

A protective group of amino includes for example formyl, (C₁₋₆alkyl)carbonyl (acetyl, propionyl, butyryl, isobutyryl, valeryl,isovaleryl, pivaloyl, etc.), carbamoyl, C₁₋₆ alkoxycarbonyl(methoxycarbonyl, ethoxycarbonyl, isopropyloxycarbonyl,sec-butoxycarbonyl, t-butoxycarbonyl, etc.), substituted silyl(trimethylsilyl, triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl,t-butyldiphenylsilyl, etc.), aralkyloxycarbonyl (benzyloxycarbonyl.9-fluorenylmethyloxycarbonyl, etc.) allyl, and aralkyl.

The leaving group includes, for example, a halogen atom, acetyloxy,trifluoroacetyloxy, methanesulfonyloxy, paratoluenesulfonyloxy.

Step A1-1a:

Compound a1 may be obtained by reacting Compound a with a base.

Examples of the base include metal hydrides such as sodium hydride,potassium hydride, lithium hydride; and metal alkoxides such aspotassium t-butoxide, sodium t-butoxide, lithium t-butoxide, potassiumt-pentoxide, sodium t-pentoxide, and lithium t-pentoxide. A metalalkoxide such as potassium t-butoxide is preferred.

Examples of the solvent include ether-based solvents such astetrahydrofuran (THF), diethyl ether, and dioxane, and THF is preferred.

The reaction temperature is normally −30° C. to 30° C., preferably −10°C. to 10° C.

The reaction time is normally 15 min. to 5 h., preferably 30 min. to 3h.

Compound a1 may be isolated, or it may be subjected to step A1-1bwithout being isolated.

Compound a may be obtained as a commercial product from AldlabChemicals, LLC or Tokyo Chemical Industry Co., Ltd. It may also besynthesized by referring to Bioorganic Medicinal Chemistry, 1999, 7,795-809, or CN 103086955.

Note that Compound a1 may be obtained as an alkali metal salt such as apotassium salt by being brought into contact with a base used in thereaction, and such salt may be subjected to the next step.

Step A1-1b:

Compound a1 may be reacted with Compound a2 to obtain Compound b. Thisreaction may preferably be performed in the presence of an acid.

Examples of the acid include, for example, acids such as hydrochloricacid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, andsalts of a weak base and a strong acid such as pyridine-hydrochloricacid salt.

Examples of the solvent include hydrocarbon-based solvents (hexane,heptane, benzene, toluene, xylene, etc.) and alcohol-based solvents(methanol, ethanol, etc.). Further, water may exist in the reactionmixture.

The reaction temperature is normally 40° C. to 200° C., preferably 60°C. to 150° C.

The reaction time is normally 6 min. to 30 h., preferably 30 min. to 3h.

Compound a2 may be commercially obtained as a salt with hydrogenchloride attached to it from Alfa Aesar, etc. By referring to Synlett,2011, 17, 2555-2558, Compound a2 whose hydrazine portion is protectedwith t-butoxycarbonyl may be put to use after it is deprotected with anacid such as methanesulfonic acid. Also, by referring to Journal ofMedicinal Chemistry 2003, 46, 1546-1553, Compound a2 may be synthesizedby using compound. Q¹-NH₂ as the starting compound.

Step A1-2:

Compound b may be reacted with Compound b1 or Compound b2 in thepresence of a base to obtain Compound c.

Examples of the base include tertiary amines (triethylamine,N-methylmorpholine, diisopropylethylamine, DBU, DABCO, etc.),nitrogen-containing aromatic compounds (pyridine, dimethylaminopyridine,picoline, (2,6-)lutidine, pyrazine, pyridazine, etc.), metal hydridessuch as sodium hydride, potassium hydride, lithium hydride; and metalalkoxides such as potassium t-butoxide, sodium t-butoxide, lithiumt-butoxide, potassium t-pentoxide, sodium t-pentoxide, and lithiumt-pentoxide. When using Compound b2, a metal alkoxide such as potassiumt-butoxide is preferred.

Examples of solvents that may be used include alcohol-based solventssuch as methanol, and ethanol; ether-based solvents such as THF, anddiethyl ether; ester-based solvents such as ethyl acetate, and methylacetate; nitrile-based solvents such as acetonitrile, benzonitrile, andbenzyl cyanide; amide-based solvents such as N,N-dimethyl acetamide(DMA), N,N-dimethylimidazolidinone (DMI), and DMF. An amide-basedsolvent such as DMA is preferred.

The reaction temperature is normally −50° C. to 70° C., preferably −30°C. to 50° C.

The reaction time is normally 15 min. to 72 h., preferably 1 h. to 30 h.

Compound b1 may be commercially obtained from Enamine LTD., etc. Byreferring to WO 2006/048727, Compound b1 may be synthesized by reactingcompound: H₂NCH₂CH(OP^(3a))(OP^(3b)) and phosgene or triphosgene.Compound b2 may be commercially obtained from UkrOrgSyntez Ltd., etc. Byreferring to WO 99/50262, Compound b2 may be synthesized by reactingcompound: H₂NCH₂CH(OP^(3a))(OP^(3b)) and diisocyanate such as CDI.

Step A1-3:

Compound c may be reacted with an acid to obtain Compound d.

Examples of the acid include inorganic acid (hydrochloric acid,hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid,etc.), sulfonic acid (methanesulfonic acid, benzenesulfonic acid,toluenesulfonic acid, etc.), and carboxylic acid (formic acid (FA),acetic acid, oxalic acid, maleic acid, fumaric acid, citric acid, malicacid, succinic acid, malonic acid, gluconic acid, mandelic acid, benzoicacid, salicylic acid, fluoroacetic acid, trifluoroacetic acid (TFA),tartaric acid, propionic acid, glutaric acid, etc.).

Examples of the solvent include ether-based solvents (ether,tetrahydrofuran (THF), dioxane, dimethoxyethane, cyclopentylmethylether, etc.), aromatic hydrocarbon-based solvents (benzene, toluene,xylene, quinoline, chlorobenzene, etc.), aliphatic hydrocarbon-basedsolvents (pentane, hexane, heptane, octane, cyclohexane, etc.),amide-based solvents (N,N-dimethyl formamide, N,N-dimethyl acetamide,N-methylpyrrolidone), alcohol-based solvents (methanol, ethanol,2,2,2-trifluoroethanol, n-propanol, isopropanol, n-butanol, sec-butanol,pentanol, hexanol, cyclopropanol, cyclobutanol, cyclopentanol,cyclohexanol, ethylene glycol, 1,3-propanediol, 1,4-butanediol,1,5-pentanediol, etc.), acetate ester-based solvents (methyl acetate,ethyl acetate, isopropyl acetate), acetonitrile, and a mixed solventthereof. An ether-based solvent such as tetrahydrofuran is preferred.

The reaction temperature is normally 0° C. to 100° C., preferably 10° C.to 80° C.

The reaction time is normally 10 min. to 20 h., preferably 30 min. to 5h.

Step A1-4:

a) When Z² is C₁₋₆ alkyl, C₃₋₁₅ cycloalkyl and 3 to 12 memberedheterocyclyl, Compound d may be reacted with Compound dl in the presenceof a base to obtain Compound e.

Examples of the base include metal hydrides such as sodium hydride,potassium hydride, and lithium hydride; metal alkoxides such aspotassium t-butoxide, sodium t-butoxide, lithium t-butoxide, potassiumt-pentoxide, sodium t-pentoxide, and lithium t-pentoxide; and metalalkyls such as butyllithium, and ethyllithium.

Examples of the solvent include ether-based solvents (ether,tetrahydrofuran (Tf), dioxane, dimethoxyethane, cyclopentylmethyl ether,etc.), aromatic hydrocarbon-based solvents (benzene, toluene, xylene,quinoline, chlorobenzene, etc.), aliphatic hydrocarbon-based solvents(pentane, hexane, heptane, octane, cyclohexane, etc.), and amide-basedsolvents (N,N-dimethyl formamide, N,N-dimethyl acetamide,N-methylpyrrolidone, etc.).

An amide-based solvent such as N,N-dimethyl acetamide is preferred.

The reaction temperature is normally 0° C. to 150° C., preferably 20° C.to 120° C.

The reaction time is normally 15 min. to 24 h., preferably 30 min. to 5h.

b) When Z² is C₆₋₁₀ aryl and 5 to 10 membered heteroaryl, Compound d maybe reacted with Compound dl in the presence of a base, a copper catalystand a ligand, to obtain Compound e.

Examples of the base include a weak basic inorganic salt (sodiumcarbonate, potassium carbonate, potassium phosphate, cesium carbonate,etc.), and organic base (triethyl amine, pyridine, tetrabutylammoniumfluoride, etc.). A weak basic inorganic salt such as potassium carbonateis preferred.

Examples of the copper catalyst include copper iodide (I), copperbromide (I), copper chloride (I), copper acetate (I), copper oxide (II),and copper trifluoromethanesulfonate (I), and copper iodide (I) ispreferred.

Examples of the ligand include phenanthroline, quinolin-8-ol,2,2,6,6-tetramethylheptane-3,5-dione, and diamines such asN,N′-dimethylethane-1,2-diamine, trans-cyclohexane-1,2-diamine, andtrans-N,N′-dimethylcyclohexane-1,2-diamine, andtrans-N,N′-dimethylcyclohexane-1,2-diamine is preferred.

Examples of the solvent include ether-based solvents (ether,tetrahydrofuran (THF), dioxane, dimethoxyethane, cyclopentylmethylether, etc.), aromatic hydrocarbon-based solvents (benzene, toluene,xylene, quinoline, chlorobenzene, etc.), aliphatic hydrocarbon-basedsolvents (pentane, hexane, heptane, octane, cyclohexane, etc.),amide-based solvents (N,N-dimethyl formamide, N,N-dimethyl acetamide,N-methylpyrrolidone, etc.), alcohol-based solvents (methanol, ethanol,2,2,2-trifluoroethanol, n-propanol, isopropanol, n-butanol, sec-butanol,pentanol, hexanol, cyclopropanol, cyclobutanol, cyclopentanol,cyclohexanol, ethylene glycol, 1,3-propanediol, 1,4-butanediol,1,5-pentanediol, etc.), acetate ester-based solvents (methyl acetate,ethyl acetate, isopropyl acetate, etc.), and acetonitrile, and anamide-based solvent such as N-methylpyrrolidone is preferred.

The reaction temperature is normally 30° C. to 200° C., preferably 60°C. to 160° C.

The reaction time is normally 1 h. to 15 h., preferably 3 h. to 9 h.

Step A1-5:

Compound e may be deprotected to obtain Compound f.

When the protective group P^(1a) is C₁₋₆ alkoxycarbonyl such ast-butoxycarbonyl, it is preferable to use an acid for deprotection.

Examples of the acid include inorganic acid (hydrogen chloride,hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid,etc.), sulfonic acid (methanesulfonic acid, benzenesulfonic acid,toluene sulfonic acid, etc.), and carboxylic acid (formic acid, aceticacid, oxalic acid, maleic acid, fumaric acid, citric acid, malic acid,succinic acid, malonic acid, gluconic acid, mandelic acid, benzoic acid,salicylic acid, fluoroacetic acid, trifluoroacetic acid, tartaric acid,propionic acid, glutaric acid, etc.).

Examples of the solvent include ether-based solvents (tetrahydrofuran,methyltetrahydrofuran, diethyl ether, t-butylmethyl ether, diisopropylether, cyclopentylmethyl ether, 1,2-dimethoxyethane, etc.),hydrocarbon-based solvents (hexane, heptane, benzene, toluene, etc.),amide-based solvents (N,N-dimethyl formamide, N,N-dimethyl acetamide,N-methylpyrrolidone, etc.), and halogen-based solvents (dichloromethane,chloroform, carbon tetrachloride, etc.), and an amide-based solvent suchas N-methylpyrrolidone is preferred.

The reaction temperature is normally 0° C. to 200° C., preferably 10° C.to 120° C.

The reaction time is normally 30 min. to 10 h., preferably 1 h. to 6 h.

Note that Compound f may be obtained as a salt with the acid used in thereaction, and such salt may be subjected to the next step.

<General Production Method A2>

When Z² is a bulky group such as C₃₋₁₅ cycloalkyl that is substitutedwith —NR^(zd)R^(ze) it is possible to synthesize Compound pcorresponding to Compound f by General production method A2 asillustrated by the following scheme.

In the formulae, Z^(2a) is non-substituted C₃₋₁₅ cycloalkyl or 3 to 12membered heterocyclyl.

P^(1a) and P^(2a) are protective groups of amino,

X², X³, X⁴ and X⁵ are each independently a leaving group,

-   -   R^(10a) and R^(10b) are independently C₁₋₆ alkyl, or R^(10a) and        R^(10b) together with oxygen atoms to which they are attached        and a carbon atom to which the oxygen atoms are attached may        form a 5 to 7 membered 1,3-dioxacycloalkane ring.

Examples of the protective group of amino include formyl, (C₁₋₆alkyl)carbonyl (acetyl, propionyl, butyryl, isobutyryl, valeryl,isovaleryl, pivaloyl, etc.), carbamoyl, C₁₋₆ alkoxycarbonyl(methoxycarbonyl, ethoxycarbonyl, isopropyloxycarbonyl,sec-butoxycarbonyl, t-butoxycarbonyl, etc.), substituted silyl(trimethylsilyl, triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl,t-butyldiphenylsilyl, etc.), aralkyloxycarbonyl (benzyloxycarbonyl,9-fluorenylmethyloxycarbonyl, etc.), allyl, aralkyl.

Examples of the leaving group include a halogen atom, acetyloxy,trifluoroacetyloxy, methanesulfonyloxy, and paratoluenesulfonyloxy.

Step A2-1:

Compound g may be reacted with an azide in the presence of a base, toobtain Compound h.

Examples of the base include tertiary amines (triethylamine,N-methylmorpholine, diisopropylethylamine, DBU, DABCO, etc.).

Examples of the azide include metal azides such as sodium azide,trimethylsilyl azide, and diphenylphosphoryl azide, anddiphenylphosphoryl azide is preferred.

Examples of the solvent include ether-based solvents (tetrahydrofuran,methyltetrahydrofuran, diethyl ether, t-butylmethyl ether, diisopropylether, cyclopentylmethyl ether, 1,2-dimethoxyethane, etc.),hydrocarbon-based solvents (hexane, heptane, benzene, toluene, etc.),and amide-based solvents (N,N-dimethyl formamide, N,N-dimethylacetamide, N-methylpyrrolidone), and a hydrocarbon-based solvent such astoluene is preferred.

The reaction temperature is normally 0° C. to 150° C., preferably 10° C.to 100° C.

The reaction time is normally 1 h. to 10 h., preferably 2 h. to 6 h.

Compound g is described in, for example, Journal of the AmericanChemical Society, 2016, 138, 1698-1708 and WO 2009/152133. It may alsobe commercially obtained from Enamine Ltd.

Step A2-2:

Compound b obtained in Step A1-1b may be reacted with Compound h in thepresence of a base, to obtain Compound i.

Examples of the base include tertiary amines (triethylamine,N-methylmorpholine, diisopropylethylamine, DBU, DABCO, etc.), andnitrogen-containing aromatic compounds (pyridine, dimethylaminopyridine,picoline, (2,6-)lutidine, pyrazine, pyridazine, etc.).

Examples of the solvent include ether-based solvents such astetrahydrofuran (THF), diethyl ether, dioxane; and hydrocarbon-basedsolvents such as hexane, heptane, benzene, toluene, etc. A base such aspyridine may also be used as the solvent.

The reaction temperature is normally 0° C. to 60° C., preferably 5° C.to 45° C.

The reaction time is normally 30 min. to 50 h., preferably 2 h. to 10 h.

Step A2-3:

Compound i may be reacted with Compound i1 or Compound i2 in thepresence of a base to obtain Compound j.

The base includes a weak basic inorganic salt (sodium carbonate,potassium carbonate, cesium carbonate, etc.), and metal hydrides (sodiumhydride, potassium hydride, etc.), and a weak basic inorganic salt suchas cesium carbonate is preferred.

Examples of Compound i1 include 1,2-dichloro-1-methoxyethane,1,2-dichloro-1-ethoxyethane, ans 1,2-dichloro-1-i-propoxyethane, and1,2-dichloro-1-t-butoxyethane, and 1,2-dichloro-1-ethoxyethane ispreferred. Compound i1 may be commercially obtained from Tokyo ChemicalIndustry Co., Ltd. or FCH Group.

Examples of Compound i2 include 2-chloro-1,1-dimethoxyethane,2-chloro-1,1-diethoxyethane, 2-bromo-1,1-dimethoxyethane, and2-bromo-1,1-ethoxyethane. Compound i2 may be commercially obtained fromTokyo Chemical Industry Co., Ltd.

Examples of the solvent include alcohol-based solvents such as methanol,ethanol; ether-based solvents such as THF, diethyl ether; ester-basedsolvents such as ethyl acetate, methyl acetate; nitrile-based solventssuch as acetonitrile, benzonitrile, benzyl cyanide; and amide-basedsolvents such as N,N-dimethyl acetamide (DMA), N,N-dimethylimidazolidinone (DMI), DMF. An amide-based solvent such as DMA ispreferred.

The reaction temperature is normally 0° C. to 60° C., preferably 20° C.to 45° C.

The reaction time is normally 1 h. to 72 h., preferably 12 min. to 35 h.

Step A2-4:

Compound j may be reacted with acid to obtain Compound k.

Examples of the acid include an inorganic acid (hydrochloric acid,hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid,etc.), a sulfonic acid (methanesulfonic acid, benzenesulfonic acid,toluenesulfonic acid, etc.), and a carboxylic acid (formic acid, aceticacid, oxalic acid, maleic acid, fumaric acid, citric acid, malic acid,succinic acid, malonic acid, gluconic acid, mandelic acid, benzoic acid,salicylic acid, fluoroacetic acid, trifluoroacetic acid, tartaric acid,propionic acid, glutaric acid, etc.), and a sulfonic acid such asmethanesulfonic acid is preferred.

Examples of the solvent include ether-based solvents such astetrahydrofuran (THF), diethyl ether, and dioxane, and THF is preferred.

The reaction temperature is normally 0° C. to 100° C., preferably 20° C.to 80° C.

The reaction time is normally 15 min. to 6 h., preferably 30 min. to 3h.

Step A2-5:

Compound k may be reacted with Compound k1 in the presence of a base, toobtain Compound 1.

Examples of Compound k1 include C₁₋₆ alkyl halides such as methyliodide, and (C₁₋₆ alkyl)carbonyl halides such as acetyl chloride. WhenR^(zd) is (C₁₋₆ alkyl)carbonyl, it is preferred to use an acid anhydridethat is represented as ((C₁₋₆ alkyl)carbonyl)₂O, for example, an aceticanhydride in place of Compound k1.

Examples of the base include metal hydrides such as sodium hydride,potassium hydride, and lithium hydride; and metal alkoxides such aspotassium t-butoxide, sodium t-butoxide, lithium t-butoxide, potassiumt-pentoxide, sodium t-pentoxide, and lithium t-pentoxide. A metalalkoxide such as potassium pentoxide is preferred.

Examples of the solvent includes ether-based solvents such astetrahydrofuran (THF), diethyl ether, dioxane; and hydrocarbon-basedsolvents such as hexane, heptane, benzene, toluene. THF is preferred.

The reaction temperature is normally −50° C. to 50° C., preferably −40°C. to 40° C.

The reaction time is normally 1 min. to 2 h., preferably 3 min. to 30min.

Step A2-6:

Compound 1 may be deprotected to obtain Compound m.

An appropriate reagent or reaction condition may be selected accordingto the type of the protective group in deprotection. When the protectivegroup is t-butoxycarbonyl, a reaction with an acid is preferred.

Examples of the acid include inorganic acid (hydrochloric acid,hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid,etc.), sulfonic acid (methanesulfonic acid, benzenesulfonic acid,toluenesulfonic acid, etc.), and carboxylic acid (formic acid, aceticacid, oxalic acid, maleic acid, fumaric acid, citric acid, malic acid,succinic acid, malonic acid, gluconic acid, mandelic acid, benzoic acid,salicylic acid, fluoroacetic acid, trifluoroacetic acid, tartaric acid,propionic acid, glutaric acid, etc.), and carboxylic acid such astrifluoroacetic acid is preferred.

Examples of the solvent include ether-based solvents such as diethylether, THF, dimethoxyethane, etc.; halogen-based solvents such asdichloromethane (CH₂C₂), chloroform, carbon tetrachloride;N,N-dimethylformamide; and acetonitrile. A halogen-based solvent such asCH₂Cl₂ is preferred.

The reaction temperature is normally 0° C. to 60° C., preferably 10° C.to 40° C.

The reaction time is normally 30 min. to 10 h., preferably 1 h. to 5 h.

Note that Compound m may be obtained as a salt with the acid used in thereaction, and such salt may be subjected to Step A2-7.

Step A2-7:

An amino in Compound m may be protected to obtain Compound n.

An appropriate reagent or reaction condition may be selected accordingto the type of protective group in protection. When the protective groupis C₁₋₆ alkoxycarbonyl, a reaction with a base is preferred.

Examples of the compound used for protection include methoxycarbonylchloride, ethoxycarbonyl chloride, 2,2,2-trichloroethoxycarbonylchloride, benzoyl chloride (Z—Cl), 9-fluorenylmethyloxycarbonyl chloride(Fmoc-Cl), and di-t-butyl dicarbonate, and di-t-butyl dicarbonate ispreferred.

Examples of the base include tertiary amines (triethylamine,N-methylmorpholine, diisopropylethylamine, DBU, DABCO, etc.), andnitrogen-containing aromatic compounds (pyridine, dimethylaminopyridine,picoline, (2,6-)lutidine, pyrazine, pyridazine, etc.), and a tertiaryamine such as triethyl amine is preferred.

Examples of the solvent includes ether-based solvents such as diethylether, THF, dimethoxyethane, etc.; halogen-based solvents such asdichloromethane (CH₂Cl₂), chloroform, carbon tetrachloride;N,N-dimethylformamide; and acetonitrile. A halogen-based solvent such asCH₂Cl₂ is preferred.

The reaction temperature is normally 0° C. to 60° C., preferably 15° C.to 40° C.

The reaction time is normally 30 min. to 20 h., preferably 1 h. to 5 h.

Step A2-8:

Compound n may be reacted with Compound n1 in the presence of a base toobtain Compound o.

Examples of Compound n1 include C₁₋₆ alkyl halides such as methyliodide, and (C₁₋₆ alkyl)carbonyl halide such as acetyl chloride. WhenR^(ze) is C₁₋₆ alkyl, it is preferred that C₁₋₆ alkyl is either notsubstituted or substituted with C₁₋₆ alkoxy.

This step is performed similarly to Step A2-5, and the base, and solventused in the reaction, and reaction temperature, reaction time aresimilar to Step A2-5.

Step A2-9:

Compound o may be deprotected to obtain Compound p.

An appropriate reagent or reaction condition may be selected accordingto the type of protective group in deprotection. When the protectivegroup P^(1a) is C₁₋₆ alkoxycarbonyl such as t-butoxycarbonyl,deprotection using an acid is preferred.

This step is performed similarly to Step A1-5, and the acid, and solventused in the reaction, and reaction temperature, reaction time aresimilar to Step A1-5.

<General Production Method B>

It is possible to synthesize Compound bf by General production method Bas illustrated by the following scheme.

In the formulae, P²¹ is hydroxy, C₁₋₆ alkoxy, or —NR^(21a)R^(21b), andR^(21a) and R^(21b) are independently a hydrogen atom, C₁₋₆ alkyl orC₆₋₁₀ aryl,

-   -   X²¹ is a hydrogen atom, a halogen atom, or —Zn—X^(21a),    -   X^(21a) is a bromine atom or an iodine atom, and    -   X²² is a leaving group.

The leaving group includes, for example, a halogen atom, acetyloxy,trifluoroacetyloxy, methanesulfonyloxy, paratoluenesulfonyloxy.

Step B-1:

Compound ba may be reacted with Compound ba1 in the presence of aparadium catalyst to obtain Compound bb.

The complex formed in the reaction mixture by separately adding apalladium compound and a ligand may be used as the palladium catalyst.The complex that has been prepared separately may be used. Examples ofthe ligand include 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene,trimethylenebis(diphenylphosphine), 2-(di-t-butylphosphino)biphenyl,2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl,2-(di-t-butylphosphino)-2′,4′,6′-triisopropyl-3,6-dimethoxy-1,1′-biphenyl,and 2-di-t-butylphosphino-2′,4′,6′-triisopropylbiphenyl. Examples ofpalladium compounds that may be combined with a ligand include, forexample, di-μ-chlorobis[(η-allyl)palladium(II)],tetrakis(triphenylphosphine)palladium(0).

Examples of the palladium catalyst that may be used with the presentstep include tris(dibenzylideneacetone)dipalladium(0),5,10,15,20-tetraphenyl-21H,23H-porphine Cobalt(II), palladium(II)acetate,bis(di-t-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II),[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloridedichloromethane adduct, dichlorobis(triphenylphosphine)palladium(II),palladium hydroxide, tetrakis(triphenylphosphine)palladium(0), anddi-μ-chlorobis[(η-allyl)palladium(II)]. It is preferred to use a complexformed from a palladium compound ofdi-μ-chlorobis[(η-allyl)palladium(II)] and a ligand of2-(di-t-butylphosphino)-2′,4′,6′-triisopropyl-1,1′-biphenyl as acatalyst in Step 11.

Note that the step may be performed in the presence ofa base.

Examples of the base includes a weak basic inorganic salt (sodiumcarbonate, potassium carbonate, cesium carbonate, sodium acetate,potassium acetate, calcium acetate, etc.), metal hydrides (sodiumhydride, potassium hydride, etc.), and metal alkoxides (potassiumt-butoxide, sodium t-butoxide, lithium t-butoxide, potassiumt-pentoxide, sodium t-pentoxide, lithium t-pentoxide, etc.).

Examples of the reaction solvent include ether-based solvents such astetrahydrofuran (THF), diethyl ether, dioxane, etc.; amide-basedsolvents such as N,N-dimethyl acetamide (DMA),N,N-dimethylimidazolidinone (DMI), DMF. The solvent may be a mixturewith water.

The reaction temperature is normally 10° C. to 200° C., preferably 40°C. to 130° C.

The reaction time is normally 1 min. to 20 h., preferably 10 min. to 10h.

Compound ba may be obtained commercially from Aurora Fine Chemicals. Itmay also be synthesized by referring to Synthetic Communications,39(14), 2506-2515, 2009. It may also be obtained by esterifying oramidating Compound ba in which —COP²¹ is —COOH.

Compound ba1 whose X²¹ is —Zn—X^(21a) may be obtained commercially fromFocus Synthesis LLC. It may be synthesized by referring to WO2014/201206.

Step B-2:

Compound bb may be reacted with Compound bb1 in the presence of a baseto obtain Compound bc.

Examples of the base include metal hydrides such as sodium hydride,potassium hydride, etc., and alkali metal hydroxides such as lithiumhydroxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide,and potassium hydroxide is preferred.

Examples of the reaction solvent include amide-based solvents such asN,N-dimethyl acetamide (DMA), N,N-dimethylimidazolidinone (DMI), andDMF, and DMI is preferred. The solvent may be a mixture with water.

The reaction temperature is normally −10° C. to 100° C., preferably 0°C. to 45° C.

The reaction time is normally 30 min. to 10 h., preferably 1 h. to 5 h.

Compound bb may be obtained commercially from Aquila Pharmatech LLC. Itmay be synthesized by referring to WO 2013/010904, Organic Letters,7(18), 3965-3968, 2005, or U.S. Pat. No. 5,998,438.

Step B-3:

Compound be may be reacted with hydroxyamine (H₂NOH) to obtain Compoundbd.

Examples of the reaction solvent include aprotic polar solvents such asdimethylsulfoxide (DMSO), dimethylformamide, dimethylacetamide, and1-methyl-2-pyrrolidinone, and alcohol-based solvents such as methanoland ethanol, and DMSO is preferred. The solvent may be a mixture withwater.

The reaction temperature is normally −10° C. to 100° C., preferably 20°C. to 45° C.

The reaction time is normally 2 h. to 72 h., preferably 3 h. to 36 h.

Compound bd may be subjected to Step B-4 without being isolated orpurified.

Step B-4:

Compound bd may be reacted with triphosgene, chloro-carbonic acid ester(methyl chlorocarbonate, ethyl chlorocarbonate, isopropylchlorocarbonate, etc.), carbonyl diimidazole, etc., preferably carbonyldiimidazole in the presence of a base, to obtain Compound be.

Examples of the base include tertiary amines (triethyl amine,N-methylmorpholine, diisopropylethylamine, 1,8-diazabicycloundec-7-ene(DBU), DABCO, etc.), and metal hydroxides (sodium hydroxide, potassiumhydroxide), and a tertiary amine such as DBU is preferred.

Examples of the solvent include aprotic polar solvents such asdimethylsulfoxide (DMSO), dimethylformamide, dimethylacetamide, and1-methyl-2-pyrrolidinone, alcohol-based solvents such as methanol andethanol, and ether-based solvents such as tetrahydrofuran (THF), diethylether, and dioxane, and DMSO is preferred.

The reaction temperature is normally −10° C. to 100° C., preferably 20°C. to 45° C.

The reaction time is normally 10 min. to 10 h., preferably 15 min. to 2h.

Step B-5:

Compound be that is protected with P²¹ may be deprotected using a baseto obtain Compound bf.

Examples of the base include alkali metal hydroxides such as lithiumhydroxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide;and metal alkoxides such as potassium t-butoxide, sodium t-butoxide,lithium t-butoxide, potassium t-pentoxide, sodium t-pentoxide, andlithium t-pentoxide.

Examples of the solvent include alcohol-based solvents such as methanol,ethanol, methoxy ethanol, t-butylalcohol; ether-based solvents such asTHF, diethyl ether; and amide-based solvents such as N,N-dimethylacetamide (DMA), N,N-dimethylimidazolidinone (DM), and DMF. The solventmay also be a mixture with water.

The reaction temperature is normally −20° C. to 120° C., preferably 20°C. to 100° C.

The reaction time is normally 20 min. to 10 h., preferably 30 min. to 5h.

Note that the order of Steps B-1, B-2, B-3, B-4 and B-5 may be changed.For example, Compound ba may be sequentially subjected to Step B-2, andStep B-1 to obtain Compound bc. Compound ba may be sequentiallysubjected to Step B-2, Step B-3, Step B-4, Step B-5, and Step B-1 toobtain Compound bf Compound ba may be sequentially subjected to StepB-2, Step B-3, Step B-4, Step B-1 and Step B-5 to obtain Compound bf.

Step B-Aa and Step B-Ab:

Further when X²¹ is a halogen atom, Compound ba may be subjected to thefollowing Step B-Aa and Step B-Ab to obtain Compound bb, and Compound bbmay also be subjected to Step B-2.

In the formulae, R^(Qc) and R^(Qd) are independently a hydrogen atom orC₁₋₆ alkyl, or R^(Qc) and R^(Qd) together with oxygen atoms to whichthey are attached and a carbon atom to which the oxygen atoms areattached may form 1,3,2-dioxaborolanyl or 1,3,2-dioxaborinanyl.

Step B-Aa:

Compound ba may be reacted with Compound ba2 or Compound Ba3 in thepresence of a palladium catalyst to obtain an organic boron Compoundbaa. This step may be performed in the presence of a base.

This step is performed similarly to Step B-1, and the palladiumcatalyst, the base, the solvent used in the reaction, or the reactiontemperature, reaction time are similar to Step B-1.

Examples of Compound ba2 include pinacol borane,4,6,6-trimethyl-1,3,2-dioxaborinane. Compound ba3 includes, for example,diboronic acid, pinacoldiborane(4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane)),bis(neopentyl glycolato)diboron, and bis(hexylene glycolato)diboron.These compounds may be obtained as a commercial product from TokyoChemical Industry Co., Ltd. By referring to Journal of the AmericanChemical Society, 131(45), 16346-16347, 2009 or Organic Synthesis, 77,176-185, 2000, they may also be synthesized using i) pinacol and ii)diborane, BH₃·THF complex or BH₃·dimethyl sulfide complex.

The organic boron compound baa may be subjected to Step B-Ab withoutbeing isolated.

Step B-Ab:

An organic boron compound baa may be reacted with Compound ba1 in thepresence of base to obtain Compound bb.

Examples of the base include a weak basic inorganic salt (sodiumcarbonate, potassium carbonate, cesium carbonate, sodium acid carbonate,potassium acid carbonate, etc.), and sodium carbonate is preferred.

The solvent used in the reaction or the reaction temperature, reactiontime is the same as Step B-1.

Note that a transformation of Compound ba1 to an organic boron compoundsimilar to the transformation of Compound ba to Compound baa, followedby a reaction thereof with Compound ba also provides Compound bb.

Step B-B:

Further, when Compound bb1 is represented by X²¹—(CH₂)_(n1)—CH₂—CN,Compound bca corresponding to Compound be obtained in Step B-2 may besubjected to Step B-B, that is, reacted with Compound bc1 in thepresence of a base to give Compound bcb corresponding to Compound bc, inwhich R⁷ and R⁸ together with a carbon atom to which they are attachedform C₃₋₁₅ cycloalkane ring, and C₃₋₁₅ cycloalkane ring formed bycombining R⁷ and R⁸ may be substituted with one to three C₁₋₆ alkyls,and the resulting compound may be subjected to Step B-3.

In the formulae, R^(7c), R^(7e) and R^(7d) existing in a number of n8are each independently a hydrogen atom or C₁₋₆ alkyl, and n8 is aninteger of 0 to 3.

The base includes, for example, metal hydrides such as sodium hydride,potassium hydride, lithium bis(trimethylsilyl)amide (LiHMDS), and sodiumbis(trimethylsilyl)amide (NaHMDS), potassium bis(trimethylsilyl)amide(KHMDS), lithium diisopropylamide (LDA), and lithium2,2,6,6-tetramethylpyrrolidide, and KHMDS is preferred.

The solvent includes, for example, ether-based solvents such as THF,diethyl ether and dioxane, amide-based solvents such as N,N-dimethylacetamide (DMA), N,N-dimethylimidazolidinone (DMI), DMF,N,N′-dimethylpropyleneurea (DMPU), and an amide-based solvent such asDMPU is preferred.

The reaction temperature is, for example, −20° C. to 40° C., preferably−10° C. to 10° C.

The reaction time is, for example, 30 min. to 8 h., preferably 1 h. to 4h.

Compound bc1 may be obtained as a commercial product from CGeneTech.Inc. It may also be synthesized by referring to Organic Letters, 12(17),3938-3941, 2010.

<General Production Method C>

Step C-1:

Compound f (or Compound p) and Compound bf may be condensed using acondensation agent in the presence of a base, and Compound (Ia) may beobtained.

Examples of the condensation agent include BOP-based condensation agentssuch as benzotriazol-1-yloxy-tris(dimethylamino)phosphoniumhexafluorophosphate (BOP),benzotriazol-1-yloxy-tris(pyrrolizino)phosphonium hexafluorophosphate(PyBOP(Registered Trademark)), PyAOP, BroP, PyCloP, PyBroP(RegisteredTrademark), DEPBT;4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloriden-hydrate (DMT-MM), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluroniumtetrafluoroborate (TBTU),[dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylidene]-dimethylazaniumhexafluorophosphate (HATU), and ethyl (hydroxyimino)cyanoacetate(Oxyma). HATU is preferred.

Examples of the base include tertiary amines (triethyl amine,N-methylmorpholine, diisopropylethylamine, DBU, DABCO, etc.), andnitrogen-containing aromatic compounds (pyridine, dimethylaminopyridine,picoline, (2,6-)lutidine, pyrazine, pyridazine, etc.), and a tertiaryamine such as diisopropylethylamine is preferred.

Examples of the solvent include ether-based solvents such as THF,diethyl ether and dioxane, aprotic polar solvents such asdimethylsulfoxide (DMSO), dimethylformamide (DMF), dimethylacetamide,and 1-methyl-2-pyrrolidinone, and an aprotic polar solvent such as DMFis preferred.

The reaction temperature is, for example, 0° C. to 80° C., preferably20° C. to 60° C.

The reaction time is, for example, 1 min. to 10 h., preferably 30 min.to 5 h.

Note that Compound (Ia) may be obtained by changing the order of thesteps, for example, by sequentially subjecting Compound d to Step A1-5,Step C-1, Step A1-4, sequentially subjecting Compound ba to Step B-2,Step B-3, Step B-4, Step B-5, Step C-1, and Step B-1.

Further, the compound represented by Formula (I) may be brought incontact with or reacted with an acid or base that may be used in theproduction of pharmaceutical preparations to obtain the salt thereof.The salt may be any pharmaceutically acceptable salt, and examples ofsuch salts include inorganic acid salts (hydrochloric acid salt,hydrobromic acid salt, hydroiodic acid salt, sulfuric acid salt,phosphoric acid salt, etc.), sulfonic acid salts (methanesulfonic acidsalt, ethanesulfonic acid salt, benzenesulfonic acid salt, toluenesulfonic acid salt, etc.), carboxylic acid salts (formic acid salt,acetic acid salt, oxalic acid salt, maleic acid salt, fumaric acid salt,citric acid salt, malic acid salt, succinic acid salt, malonic acidsalt, gluconic acid salt, mandelic acid salt, benzoic acid salt,salicylic acid salt, fluoroacetic acid salt, trifluoroacetic acid salt,tartaric acid salt, propionic acid salt, glutaric acid salt, adipic acidsalt, nicotinic acid salt, etc.), alkali metal salts (lithium salt,sodium salt, potassium salt, cesium salt, rubidium salt, etc.), alkaliearth metal salts (magnesium salt, calcium salt, etc.), ammonium salts(ammonium salt, alkylammonium salt, dialkylammonium salt,trialkylammonium salt, tetraalkylammonium salt, etc.), and basic aminoacid salts (lysine salt, arginine salt, etc.), and alkali metal saltsand alkali earth metal salts are preferred, and sodium salts and calciumsalts are even more preferred. For example, the free form of a compoundrepresented by Formula (I) may be suspended or dissolved in alcohol,such as methanol, and ethanol, or acetonitrile, acetone,dimethylsulfoxide, etc. and a basic aqueous solution containing sodiumion from sodium hydroxide, etc., a methanol solution containing sodiummethoxide, or an ethanol solution containing sodium ethoxide is addedthereto, to obtain a sodium salt of a compound represented by Formula(I). The reaction temperature is, for example, 0° C. to 80° C.,preferably 20° C. to 60° C.

The compound represented by Formula (1) or a salt thereof may be asolvate, or a non-solvate. The solvent contained in a solvate may beeither water or an organic solvent. Alcohols (e.g. methanol, ethanol,n-propanol), dimethylformamide, acetonitrile, acetone, dimethylsulfoxidemay be used as the organic solvent. The compound represented by Formula(I) and a salt thereof may be preferably used in the form of a hydrate,and it is also preferably used in the form of a non-solvate. Theproportion of the solvent molecule (preferably a water molecule) againsta single molecule compound represented by Formula (I) or a salt thereofis, for example, 0.1 to 10, and 0.5 to 6 is more preferred. Further, theproportion may fluctuate by humidity, the production method, and theproduction season.

The solvate of a compound represented by Formula (I) or a salt thereofmay be obtained by a common method, such as precipitating the compoundrepresented by Formula (1) or a salt thereof from a solvent. Further,the hydrate may be obtained by precipitating a compound represented byFormula (I) or a salt thereof from a water-containing organic solvent.

The solvate of a compound represented by Formula (I) or a salt thereofmay be transformed to a compound represented by Formula (I) or a saltthereof by a common method such as heating under reduced pressure.

A compound used as a pharmaceutical agent is preferably the compoundrepresented by Formula (I) per se (free form), a hydrate of the freeform, a salt of the free form, and a hydrate of salt, more preferably, afree form, a hydrate of the free form, a sodium salt of the free form, ahydrate of a sodium salt, a calcium salt of the free form, and a hydrateof the calcium salt.

The compound represented by Formula (I) or a salt thereof, or a solvateof either the compound or a salt of the compound, of the presentinvention may be used in a form of a crystal, or in an amorphous state.

The present invention includes all stereoisomers of the compoundrepresented by Formula (I) (e.g. enantiomer, diastereomer (includingcis- and trans-geometric isomer)), the racemic form of the isomers, andother mixtures. For example, the compound of the present invention mayhave one or more asymmetric center, and the present invention includes aracemic mixture, a diastereomer mixture, and enantiomers of suchcompound.

The present invention includes an embodiment in which an atomconstituting the compound molecule of the present invention representedby Formula (I) is an isotope, and includes an embodiment in which atleast one atom is substituted with an atom having the same atomic number(proton number) and a different mass number (sum of protons andneutrons). Examples of isotopes included in the compound of the presentinvention include hydrogen atom, carbon atom, nitrogen atom, oxygenatom, phosphorous atom, sulfur atom, fluorine atom, chlorine atom, whichrespectively include ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S ¹⁸F,³⁶Cl. In particular, radioisotopes which emit radiation as they decay,such as ³H or ¹⁴C, are useful in pharmaceutical preparations or in vivotopographic tests of compounds. The stable isotope neither decays norchanges in their amount, nor have radioactivity, so they can be usedsafely. When the atom constituting the compound molecule of the presentinvention is an isotope, it may be transformed according to the commonmethod by replacing the reagent used in synthesis with a reagentcontaining the corresponding isotope.

The compound of the present invention, a salt thereof, or a solvent ofthese has a GLP1 receptor agonist effect and a blood glucose levelreduction effect, and it may be used for the prevention or therapy ofnon-insulin-dependent diabetes mellitus (Type 2 diabetes),hyperglycemia, impaired glucose tolerance, insulin-dependent diabetesmellitus (Type 1 diabetes), diabetic complication, obesity,hypertension, hyperlipidemia, arteriosclerosis, myocardial infarction,coronary heart disease, brain infarction, non-alcoholic steatohepatitis,Parkinson's disease, or dementia, by administering it to patients in theform of a pharmaceutical composition in pharmacologically effectiveamount by an appropriate administration method.

“Diabetes” in the present invention is a state or a disease in which themetabolism for generating and using glucose becomes deficient due to afailure in maintaining an appropriate blood glucose level in the body,and encompasses insulin-dependent diabetes mellitus (Type 1 diabetes)and non-insulin-dependent diabetes mellitus (Type 2 diabetes).

“Hyperglycemia” refers to a state in which the plasma glucose levelwhile fasting or after administration of glucose is higher than thenormal value (e.g. 80 to 110 mg/dL in human while fasting), and it is atypical symptom of diabetes.

“Impaired glucose tolerance” includes insulin-resistant impaired glucosetolerance and insulin hyposecretion.

“Diabetic complication” is a complication caused by diabetes orhyperglycemia, and it may be acute complex or chronic complex. The term“acute complex” includes ketoacidosis, and infectious disease (e.g. skininfection, soft tissue infection, biliary system infection, respiratorysystem infection, urinary tract infection), and the “chronic complex”includes, for example, microangiopathy (e.g. nephropathy, retinopathy),neuropathy (e.g. sensory nerve disorder, motor nerve disorder, autonomicnerve disorder), and gangrene.

Major diabetes complexes include diabetic retinopathy, diabeticnephropathy, and diabetic neuropathy. “Coronary heart disease” includesmyocardial infarction and angina pectoris.

“Dementia” includes, for example, Alzheimer's disease, vasculardementia, and diabetic dementia.

The administration method may be systemic administration including oraladministration, rectal administration, intravenous administration,intramuscular administration, subcutaneous administration, intravaginaladministration, intraperitoneal administration, intravesicaladministration, and aspiration, as well as local administration byointment, gels, and cream.

When using the compound of the present invention, a salt thereof, or asolvate of either the compound or a salt of the compound in the form ofa pharmaceutical composition, it is normally formulated into a certainpharmaceutical formulation (dosage form). Examples of suchpharmaceutical formulations include a tablet, a capsule, granules,powders, subtle granules, pills, aqueous or non-aqueous solution orsuspension. Further, the compound of the present invention, a saltthereof, or a solvate of either the compound or a salt of the compoundmay also be used in the form of various controlled release preparations.

Examples of such controlled release preparations include, for example,those to be imbedded in the body, those applied to the oral mucosa ornasal mucosa. The solution or suspension may be filled in containerssuited for dividing into respective administration amounts to be stored.

The various pharmaceutical formulations may be produced by a well knownmethod by mixing the compound of the present invention, a salt thereof,or a solvate of either the compound or a salt of the compound and apharmaceutically acceptable additive. Examples of such additivesinclude, for example, an excipient, a lubricant (a coating agent), abinding agent, a disintegrator, a stabilizer, correctives, a base, adispersant, a diluent, a surfactant, or an emulsifier.

Examples of an excipient include starch (starch, potato starch, cornstarch, etc.), lactose, crystalline cellulose, and dicalcium phosphate.

Examples of a lubricant (coating agent) include ethyl cellulose,hydroxypropyl cellulose, hydroxypropylmethyl cellulose, shellac, talc,carnauba wax, and paraffin.

Examples of a binding agent include polyvinyl pyrrolidone, macrogol, andcompounds that are the same as the above excipient.

Examples of a disintegrator include chemically modified starch andcellulose, such as croscarmellose sodium, sodium carboxymethyl starch,cross-linked polyvinyl pyrrolidone, and compounds that are the same asthe above excipient.

Examples of a stabilizer include para-oxybenzoates such as methylparaben, and propyl paraben; benzalkonium chloride; phenols such asphenol, and cresol; thimerosal; dehydroacetic acid; and sorbic acid.

Examples of a correctives include sweetener, acidulant, and flavor, thatare normally used.

Examples of a base include fats such as lard; vegetable oil such asolive oil and sesame oil; higher alcohols such as stearyl alcohol, andcetanol; animal oil; lanolin acid; Vaseline; paraffin; bentonite;glycerin; and glycol oil.

Examples of a dispersant include cellulose derivative (Arabic rubber,tragacanth, methyl cellulose, etc.), stearic acid polyesters, sorbitansesquioleate, aluminum monostearate, sodium alginate, polysorbate, andsorbitan fatty acid ester.

Examples of the solvent or diluent in a liquid formulation includephenol, chlorocresol, purified water, distilled water, etc.

Examples of a surfactant or emulsifier include polysorbate 80, polyoxyl40 stearate, lauromacrogol.

The content of the compound of the present invention, a salt thereof, ora solvate of either the compound or a salt of the compound in thepharmaceutical formulation differs by the dosage form, but it isgenerally 0.01 to 100 wt %.

The pharmaceutical formulation may contain one type or two or more typesof the compound of the present invention, a salt thereof, or a solvateof either the compound or a salt of the compound.

When using the compound of the present invention, a salt thereof, or asolvate of either the compound or a salt of the compound as apreventative agent or a therapeutic agent for non-insulin-dependentdiabetes mellitus (Type 2 diabetes) or obesity, the amount to beadministered may be appropriately determined according to the severityof the symptom, the age, the body weight, the relative health state,whether other drugs are combined, and the method of administration. Forexample, when the subject of administration is a homeotherm,particularly a human, the dosage per day is 0.01 to 10000 mg, preferably0.1 to 1000 mg, in oral administration, and 0.001 to 3000 mg, preferably0.01 to 300 mg in a non-oral administration. Note that the above dosagemay be administered once per a day to a few weeks, or it may be dividedinto two or more times per day.

The effective amount of the compound of the present invention, a saltthereof, or a solvate of either the compound or a salt of the compoundmeans a therapeutic effective amount or a preventative effective amount,and it may be appropriately determined according to the severity of thesymptom, the age, the body weight, the relative health state, whetherother drugs are combined, and the method of administration

EXAMPLES

The content of the present invention is explained in more detail by thefollowing Examples and Reference Examples. All starting materials andreagents were obtained from commercial suppliers or synthesized bycommonly known methods. A room temperature (rt) is a temperature of 5 to35° C. The silica gels that were used were SHOKO ScientificPurif-Pack(Registered Trademerk) SI 60 μm (Shoko Scientific Co., Ltd.),Biotage (Registered Trademark) SNAP Ultra Silica Cartridge (Biotage), orSNAP KP-Sil Cartridge (Biotage), reversed-phase silica gel was Wakosil(Registered Trademark) 25C18 (Wako Pure Chemical Industries, Ltd.), orBiotage (Registered Trademark) SNAP Ultra C18 Cartridge (Biotage). TheHPLC purification of the compound was performed using AutoPurificationHPLC/MS System (Waters) or Preprative HPLC system withinjection/fractionation function (gilson). The ¹H-NMR spectrum wasmeasured using or not using Me₄Si as an inner reference material, andusing ECP-400 (JEOL), Agilent 400-MR (Agilent Technologies Japan, Ltd),AVANCE3 300 MHz (Bruker) or AVANCE3 600 MHz Cryo-TCI (Bruker)(s=singlet, brs=broad singlet, d=doublet, t=triplet, q=quartet,dd=double doublet, ddd=double double doublet, m=multiplet). The chemicalshift of the NMR data uses Me₄Si or deuterized solvent as a reference,and is presented using ppm (parts per million, 6), and the couplingconstant (J) was shown using Hz (Hertz). LC/MS was carried out bymeasuring the retention time and performing mass spectrometry using thedevice and the analysis condition of Table 1. Microwave was irradiatedusing Initiator™ (Biotage). The mass spectrometry in LC/MS was performedusing the following mass spectrometers: SQD (Waters), SQD2 (Waters),2020 (Shimadzu), or 2010EV (Shimadzu).

TABLE 1 Device and Analysis Condition used for LC/MS LC/MS AnalysisCondition Mobile phase, gradient No. Device Column and flow rate SMD-nexera/ Speed Core C18 0.1% FA H₂O/0.1% FA FA05-1 2020 2.1 mmI.D. × 50mm, MeCN = 95/5→0/100 2.7 μm (1.5 min.)→0/100 (0.5 min.), 1 mL/min. SMD-nexera/ Metoric Core C18 0.1% FA H₂O/0.1% FA FA05-2 2020 2.1 mmI.D. × 50mm, MeCN = 95/5→0/100 2.7 μm (1.5 min.)→0/100 (0.5 min.), 1 mL/min. SMD-nexera/ Ascentis Express C18 0.1% FA H₂O/0.1% FA FA05-3 2020 2.1 mmI.D.× 50 mm, MeCN = 95/5→0/100 2.7 μm (1.5 min.)→0/100 (0.7 min.), 1 mL/min.SMD- nexera/ Speed Core C18 0.1% FA H₂O/0.1% FA FA05- 2020 2.1 mmI.D. ×50 mm, MeCN = 05/95→0/100 long 2. 7m (4.5 min.)→0/100 (0.5 min.), 1mL/min. SMD- UFLCXR/ Phenomenex kinetex 0.1% FA H₂O/0.1% FA FA10-1 2020C18 MeCN = 90/10→0/100 3.0 mmI.D. × 50 mm, (1.2 min.)→0/100 2.6 μm (0.5min.), 1.5 mL/min. SMD- UFLCXR/ Kinetex XB-C18 0.1% FA H₂O/0.1% FAFA10-2 2020 3.0 mmI.D. × 50 mm MeCN = 90/10→0/100 2.6 μm (1.2min.)→0/100 (0.5 min.), 1.5 mL/min. SMD- UFLCXR/ Kinetex XB-C18 0.1% FAH₂O/0.1% FA10-3 2020 3.0 mmI.D. × 50 mm, FA MeCN = 2.6 μm 90/10→0/100(1.1 min.)→0/100 (0.7 min.), 1.5 mL/min. SMD- UFLCXR/ Acquity BEH C180.1% FA H₂O/0.1% FA FA10-4 2020 2.1 mmI.D. × 50 mm, MeCN =90/10→0/1001.7 μm (1.1 min.)→0/100 (0.5 min.), 0.7 mL/min. SMD- Nexera/ Accucore0.1% FA H₂O/0.1% FA FA10-5 2020 2.1 mmI.D. × 50 mm, MeCN = 90/10→0/1002.7 μm (1.1 min.)→0/100 (0.5 min.), 1.0 mL/min. SMD- UFLCXR/ KinetexXB-C18 0.1% FA H₂O/0.1% FA FA1060- 2020 3.0 mmI.D. × 50 mm, MeCN =90/10→40/60 1 2.6 μm (4.0 min.)→5/95 (0.5 min.), 1.5 mL/min. SMD-UFLCXR/ Phenomenex kinetex 0.1% FA H₂O/0.1% FA FA10- 2020 C18 MeCN =90/10→0/100 long 3.0 mmI.D. × 50 mm, (4.5 min.)→0/100 2.6 μm (1.3 min.),1.1 mL/min. SMD- nexera/ Ascentis Express 0.05% TFA H₂O/0.05% TFA05-2020 C18 TFA MeCN = 1 2.1 mmI.D. × 50 mm, 95/5→0/100 2.7 μm (1.5min.)→0/100 (0.5 min.), 1 mL/min. SMD- nexera/ Metoric Core C18 0.05%TFA H₂O/0.05% TFA05- 2020 2.1 mmI.D. × 50 mm, TFA MeCN = 2 2.7 μm95/5→0/100(1.5 min.)→0/100(0.5 min.), 1 mL/min. SMD- nexera/ Kinetex 1.7u C18 0.05% TFA H₂O/0.05% TFA05- 2020 2.1 mmI.D. × 50 mm, TFA MeCN = 31.7 μm 95/5→0/100 (1.5 min.)→0/100 (0.5 min.), 1 mL/min. SMD- nexera/Ascentis Express 0.05% TFA H₂O/0.05% TFA05- 2020 C18 TFA MeCN = 4 2.1mmI.D. × 50 mm, 95/5→0/100 2.7 μm (1.1 min.)→0/100 (0.5 min.), 1 mL/min.SMD- UFLCXR/ Shim-pack XR-ODS 0.05% TFA H₂O/0.05% TFA05- 2020 3.0 mmI.D.× 50 mm, TFA MeCN = 5 2.2 μm 95/5→0/100(1.2 min.)→0/100 (1.0 min.), 1mL/min. SMD- UFLCXR/ Shim-pack XR-ODS 0.05% TFA H₂O/0.05% TFA05- 20203.0 mmI.D. × 50 mm, TFA MeCN = 6 2.2 μm 95/5→0/100 (2.2 min.)→0/100 (1.0min.), 1 mL/min. SMD- nexera/ Ascentis Express 0.1% FA H₂O/0.1% FA FA05-2020 RP-Amide MeCN = 95/5→0/100 RP 2.1 mmI.D. × 50 mm, (1.5 min.)→0/1002.7 μm (0.5 min.), 1 mL/min. SMD- nexera/ Ascentis Express 0.1% FAH₂O/0.1% FA FA50- 2020 RP-Amide MeCN = 50/50→0/100 RP 2.1 mmI.D. × 50mm, (1.0 min.)→0/100 2.7 μm (1.0 min.), 1 mL/min. SMD- nexera/ AscentisExpress 0.05% TFA H₂O/0.05% TFA05- 2020 RP-Amide TFA MeCN = RP 2.1mmI.D. × 50 mm, 95/5→0/100 2.7 μm (1.5 min.)→0/100 (0.5 min.), 1 mL/min.SMD- nexera/ Ascentis Express 0.05% TFA H₂O/0.05% TFA50- 2020 RP-AmideTFAM eCN = RP 2.1 mmI.D. × 50 mm, 50/50→0/100(1 min.)→ 2.7 μm 0/100 (1min.), 1 mL/min. SQD- Aquity Ascentis Express 0.1% FA H₂O/0.1% FA FA05-1UPLC- C18 MeCN = 95/5→0/100 I-Class/ 2.1 mmI.D. × 50 mm, (1.0min.)→0/100 SQD 2.7 μm (0.4 min.), 0.9 mL/min. SQD- Aquity AscentisExpress 0.1% FA H₂O/0.1% FA FA05-2 UPLC- RP-Amide MeCN = 95/5→0/100I-Class/ 2.1 mmI.D. × 50 mm, (1.0 min.)→0/100 SQD 2.7 μm (0.4 min.), 1mL/min. SQD- Aquity Ascentis Express 0.1% FA H₂O/0.1% FA FA05-3 UPLC/C18 MeCN = 95/5→0/100 SQD 2.1 mmI.D. × 50 mm, (1.0 min.)→0/100 2.7 μm(0.4 min.), 1 mL/min. SQD- Aquity Ascentis Express 0.1% FA H₂O/0.1% FAFA05-4 UPLC/ C18 MeCN = 95/5→0/100 SQD2 2.1 mmI.D. × 50 mm, (1.0min.)→0/100 2.7 μm (0.4 min.), 1 mL/min. SQD- Aquity Ascentis Express0.1% FA H₂O/0.1% FA FA50-1 UPLC- RP-Amide MeCN = 50/50→0/100 I-Class/2.1 mmI.D. × 50 mm, (0.7 min.)→0/100 SQD 2.7 μm (0.7 min.), 1 mL/min.SQD- Aquity Ascentis Express 10 mMAcONH₄H₂O/ AA05-1 UPLC- C18 MeOH =95/5→ I-Class/ 2.1 mmI.D. × 50 mm, 0/100(1 min.)→ SQD 5 μm 100(0.4min.), 1 mL/min. SQD- Aquity Ascentis Express 10 mMAcONH₄ AA05-2 UPLC/C18 H₂O/MeOH = SQD 2.1 mmI.D. × 50 mm, 95/5-0/100(1 min.)→ 2.7 μm100(0.4 min.), 1 mL/min. SQD- Aquity Ascentis Express 10 mMAcONH₄ H₂O/AA50-1 UPLC/ C18 MeOH = 50/50→0/100 SQD 2.1 mmI.D. × 50 mm, (0.7min.)→100 2.7 μm (0.7 min.), 1 mL/min. SQD- Aquity Ascentis Express 0.1%FA H₂O/0.1% FA FA05- UPLC- C18 MeCN = 95/5→0/100 long I-Class/ 2.1mmI.D. × 50 mm, (4.5 min.)→0/100 SQD 2.7 μm (0.5 min.), 1 mL/min. SQD-Aquity Ascentis Express 0.1% FA H₂O/0.1% FA FA0550- UPLC- C18 MeCN95/5→5/50 long I-Class/ 2.1 mmI.D. × 50 mm, (4.5 min.)→0/100 SQD 2.7 μm(0.01 min.)→0/100 (0.49 min.), 1 mL/min. SQD- Aquity Ascentis Express 10mMAcONH₄ H₂O/ AA50- UPLC- C18 MeOH = 50/50→0/100 long I-Class/ 2.1mmI.D. × 50 mm, (4.5 min.)→100 SQD 5 μm (0.5 min.), 1 mL/min. SQD-Aquity Ascentis Express 10 mMAcONH₄ H₂O/ AA0550- UPLC- C18 MeOH95/5→50/50 long I-Class/ 2.1 mmI.D. × 50 mm, (4.5 min.)→0/100 SQD 5 μm(0.01 min.)→0/100 (0.49 min.), 1 mL/min.

<Example 1> Synthesis of3-[(1S,2S)-1-[2-[2-(3,5-dimethylphenyl)-3-[3-(1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(2-ethyl-3-methylpyridin-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one(Compound 1)

<Step 1-1>

Potassium [(5-Cyano-1,2,3,6-tetrahydropyridin-4-yl)amide] (Compound 1b)

To a tetrahydrofuran (THF) (179 mL) solution of3-(2-cyanoethylamino)propanenitrile (Compound 1a, 22.0 g, 179 mmol) wasadded a THF solution (179 mL) of 1M potassium tert-butoxide and themixture was stirred at room temperature for 1 h. The reaction mixturewas filtered by washing with THF (50 mL), and then the filtrate wasdried under reduced pressure to obtain the titled Compound 1b (23.8 g,yield 83%) as a light brown solid.

LC/MS Mass Spectrometry: m/z 124 ([M+H]⁺)

LC/MS Retention Time: 0.14 min. (Analysis Condition:SMID-FA05-1).

¹H-NM/R (400 MHz, MeOH-d₄) δ:3.33 (2H, t, J=1.3 Hz), 2.90 (2H, t, J=5.9Hz), 2.21 (2H, tt, J=5.9, 1.3 Hz).

<Step 1-2>

tert-Butyl3-amino-2-(3,5-dimethylphenyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate(Compound 1d)

To an ethanol (57.9 mL) solution of 3,5-dimethylphenylhydrazinehydrochloride (Compound 1c, 5.00 g, 29.0 mmol) and Compound 1b obtainedin Step 1-1 (4.67 g, 29.0 mmol) was added 2N hydrochloric acid (23.2 mL,46.3 mmol), and the mixture was stirred at 50° C. for 1 h. After thereaction mixture was cooled to 0° C., 5M sodium hydroxide aqueoussolution (9.27 mL, 46.3 mmol) and di-tert-butyl dicarbonate (6.64 g,30.4 mmol) were added and the mixture was stirred at 0° C. for 1 h.Water was added to the reaction mixture and extraction was performedusing ethyl acetate, then the organic layer was washed with brine anddried with anhydrous magnesium sulfate. After filtration, the filtratewas concentrated under reduced pressure, and the residue was purified bya silica gel column chromatography (ethyl acetate/hexane=0:1 to 1:1) toobtain the titled Compound 1d (7.82 g, yield 79%) as a pale yellowsolid.

LC/MS Mass Spectrometry: m/z 343 ([M+H]⁺).

LC/MS retention time: 0.99 min. (Analysis condition: SMD-FA05-3).

<Step 1-3>

tert-Butyl3-(2,2-dimethoxyethylcarbamoylamino)-2-(3,5-dimethylphenyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate(Compound 1f)

To a pyridine (7.39 mL) solution of Compound 1d (2.53 g, 7.39 mmol)obtained in Step 1-2 was added 2-isocyanato-1,1-dimethoxyethane(Compound 1e, 1.94 g, 14.8 mmol), and the mixture was stirred at roomtemperature. After 3 hours and 15 minutes, diethylamine (1.08 g, 14.8mmol) was added and the mixture was stirred at room temperature for 5min., then water (50.6 mL) was added, and the resulting mixture wasstirred at room temperature for 20 min. The reaction mixture that hadbecome a suspension was filtered, and the obtained solid was washed withwater (12.7 mL) then dried under reduced pressure to obtain the titledCompound 1f (3.20 g, yield 91%) as a pale yellow solid.

LC/MS mass spectrometry: m/z 474 ([M+H]⁺).

LC/MS retention time: 0.78 min. (Analysis Condition: SQD-FA05-1).

<Step 1-4>

3-[2-(3,5-Dimethylphenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-1H-imidazol-2-one(Compound 1g)

To Compound 1f (158 mg, 0.334 mmol) obtained in Step 1-3 was addedformic acid (3.84 mL, 100 mmol), and the mixture was stirred at roomtemperature for 21 h. The reaction mixture was concentrated underreduced pressure, and toluene was added and the solvent was removed byevaporation under reduced pressure. Dichloromethane (1 mL) was added tothe residue to dissolve the residue, and then hydrogen chloride (4Mdioxane solution, 0.835 mL, 3.34 mol) was added at room temperature. Thereaction mixture was concentrated under reduced pressure. Toluene wasadded and the solvent was removed by evaporation under reduced pressureto obtain a crude product (176 mg) of the titled Compound 1g.

LC/MS mass spectrometry: m/z 310 ([M+H]⁺).

LC/MS retention time: 0.39 min. (Analysis Condition: SQD-FA05-3).

<Step 1-5>

4-Bromo-2-ethyl-3-methylpyridine (Compound 1i)

A THF (75.0 mL) solution of 4-bromo-2,3-dimethylpyridine (Compound 1h,7.05 g, 37.9 mmol) was cooled to −78° C., and then 1.11 M lithiumdiisopropylamide n-hexane-THF solution (35.8 mL, 39.8 mmol) was addedslowly. The reaction mixture was stirred at −78° C. for 5 min., and theniodomethane (2.84 mL, 45.5 mmol) was added. The reaction mixture wasstirred at −78° C. for 5 min., and warmed slowly to room temperature.Then, the reaction mixture was stirred for 30 min. and the solvent wasremoved by evaporation under reduced pressure. The residue was purifiedby silica gel column chromatography (dichloromethane/ethyl acetate), andthe titled Compound 1i (6.98 g, yield 92%) was obtained as an orangeoil-like material.

LC/MS mass spectrometry: m/z 200 ([M+H]⁺).

LC/MS retention time: 0.38 min. (Analysis Condition: SQD-FA05-3).

<Step 1-6>

Ethyl5-bromo-1-[(1S,2S)-1-cyano-2-methylcyclopropyl]indole-2-carboxylate(Compound 1l)

The N,N′-dimethylpropyleneurea (117 mL) solution of ethyl5-bromo-1-(cyanomethyl)indole-2-carboxylate (Compound 1j, 3.60 g, 11.7mmol) and (4R)-4-methyl-1,3,2-dioxathiolane 2,2-dioxide (Compound 1k,4.86 g, 35.2 mmol) was deaerated under reduced pressure, then nitrogenwas introduced in the vessel and the mixture was cooled to 0° C. Undernitrogen atmosphere, a THF solution (46.9 mL, 46.9 mmol) of 1.0 Mpotassium bis(trimethylsilyl)amide was added dropwise slowly. Thereaction mixture was stirred at 0° C. for 2.5 h., then formic acid (5.30mL, 141 mmol) was added and extraction was performed using a mixture ofhexane/ethyl acetate (1:3). The organic layer was washed three timeswith water, twice with a saturated aqueous solution of sodium hydrogencarbonate, and once with brine, and then dried with sodium sulfate.After filtration, the filtrate was concentrated under reduced pressureand the residue was purified by silica gel column chromatography (ethylacetate/hexane=1:19 to 1:4) to obtain the titled Compound 1l (1.70 g,yield 42%) as a white solid.

LC/MS mass spectrometry: m/z 347 ([M+H]⁺).

LC/MS retention time: 0.69 min. (Analysis Condition: SQD-AA50-1).

<Step 1-7>

Ethyl1-[(1S,2S)-1-cyano-2-methylcyclopropyl]-5-(2-ethyl-3-methylpyridin-4-yl)indole-2-carboxylate(Compound 1m)

The dioxane (44 mL) suspension of Compound 1l (2.70 g, 7.78 mmol)obtained in Step 1-6,4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (2.17 g,8.55 mmol) and potassium acetate (1.15 g, 11.7 mmol) were deaeratedunder reduced pressure, and then nitrogen was introduced in the vessel.Under nitrogen atmosphere, 1,1′-bis(diphenylphosphino)ferrocene-palladium (II) dichloride-dichloromethanecomplex (1.29 g, 1.56 mmol) was added, and the mixture was stirred at100° C. for 3 h. After the solution was cooled to room temperature,4-bromo-2-ethyl-3-methylpyridine (Compound 1i, 2.33 g, 11.7 mmol),sodium carbonate (2.47 g, 23.3 mmol), and water (7.4 mL) were added tothe solution, and then the solution was subjected to deaeration underreduced pressure. Nitrogen was introduced in the vessel, and thesolution was stirred at 100° C. for 2 h. The solution was cooled to roomtemperature, and then water (5.4 mL), and N-acetyl cysteine (0.635 g,3.89 mmol) were added. The mixture was stirred for 0.5 h. The reactionmixture was subjected to extraction with ethyl acetate, and the organiclayer was washed once with brine, and then dried using sodium sulfate.After filtration, the filtrate was concentrated under reduced pressureand the residue was purified by silica gel column chromatography (ethylacetate/hexane=1:19 to 2:3) to obtain the titled Compound 1m (2.92 g,yield 97%) as a pale yellow gum-like product.

LC/MS mass spectrometry: m/z 388 ([M+H]⁺).

LC/MS retention time: 1.06 min. (Analysis Condition: SQD-AA05-2).

<Step 1-8>

Ethyl5-(2-ethyl-3-methylpyridin-4-yl)-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carboxylate(Compound 1n)

To a dimethylsulfoxide (DMSO) (2.9 mL) solution of Compound 1m (0.225 g,0.581 mmol) obtained in Step 1-7 was added 50% hydroxyamine aqueoussolution (0.356 mL, 5.81 mmol), and the mixture was stirred at roomtemperature for 17 h. Ethyl acetate (50 mL) was added, the mixture waswashed with water (10 mL) and brine (10 mL), and then dried withmagnesium sulfate. After the mixture was filtered, the filtrate wasconcentrated under reduced pressure, and the obtained residue wasdissolved in DMSO (1.9 mL). Then, carbonyl diimidazole (188 mg, 1.16mmol) and 1,8-diazabicycloundec-7-ene (0.219 mL, 1.45 mmol) were addedand the resulting mixture was stirred at room temperature for 0.5 h.Formic acid was added to the mixture, which was then purified byreversed-phase chromatography (acetonitrile/water, 0.1% formic acid) toobtain the titled Compound 1n (169 mg, yield 65%) as a white powder.

LC/MS mass spectrometry: m/z 447 ([M+H]⁺).

LC/MS retention time: 0.80 min. (Analysis Condition: SMD-FA05-3).

<Step 1-9>

5-(2-Ethyl-3-methylpyridin-4-yl)-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carboxylicacid (Compound 1o)

To a DMSO (40 mL) solution of Compound 1n (3.61 g, 8.08 mmol) obtainedin Step 1-8 was added 2M sodium hydroxide aqueous solution (10.1 mL,20.2 mmol), and the mixture was stirred at room temperature for 1.5 h.Formic acid was added to the mixture, which was then purified byreversed-phase chromatography (acetonitrile/water, 0.1% formic acid) toobtain the titled Compound 10 (3.38 g, yield 100%) as a white powder.

LC/MS mass spectrometry: m/z 419 ([M+H]⁺).

LC/MS retention time: 0.83 min. (Analysis Condition: SQD-AA05-2).

<Step 1-10>

3-[(1S,2S)-1-[2-[2-(3,5-dimethylphenyl)-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(2-ethyl-3-methylpyridin-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one(Compound 1p)

To a N,N′-dimethylformamide (DMF) (24.1 mL) solution of Compound 1g(1.25 g, 3.61 mmol) obtained in Step 1-4, Compound 10 (1.59 g, 3.80mmol) obtained in Step 1-9, and[dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylidene]-dimethylazaniumhexafluorophosphate (1.51 g, 3.98 mmol) was added diisopropylethylamine(3.15 mL, 18.1 mmol), and the mixture was stirred at room temperaturefor 30 min. The reaction mixture was directly purified by reversed-phasecolumn chromatography (acetonitrile/water, 0.1% formic acid) and thetitled Compound 1p (2.44 g, yield 95%) was obtained as a light brownfoam.

LC/MS mass spectrometry: m/z 710 ([M+H]⁺).

LC/MS retention time: 0.85 min. (Analysis Condition: SMD-FA05-3).

<Step 1-11>

3-[(1S,2S)-1-[2-[2-(3,5-Dimethylphenyl)-3-[3-(1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(2-ethyl-3-methylpyridin-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one(Compound 1)

To a N-methylpyrrolidone (0.188 mL) suspension of Compound 1p (20 mg,0.028 mmol) obtained in Step 1-10, 5-bromo-1-methylindazole (Compound1q, 11.9 mg, 0.056 mmol),(1S,2S)-1-N,2-N-dimethylcyclohexane-1,2-diamine (1.6 mg, 0.011 mmol) andpotassium carbonate (11.7 mg, 0.085 mmol) was added copper (I) iodide(1.1 mg, 0.0056 mmol) at room temperature, and the mixture was stirredunder nitrogen atmosphere at 130° C. for 3 h. The reaction mixture waspurified by reversed-phase silica gel chromatography(acetonitrile/water, 0.1% formic acid), and the titled Compound 1 (17.2mg, yield 73%) was obtained as a light brown foam.

LC/MS mass spectrometry: m/z 840 ([M+H]⁺).

LC/MS retention time: 1.12 min. (Analysis Condition: SMD-TFA05-3).

Examples 2 to 50

An operation similar to Step 1-11 of Example 1 was performed using acombination of the 2-oxoimidazole compound shown in Table 2-2 and thehalogen compound shown in Table 2-3 below, as well as an appropriatereagent, and Example Compounds 2 to 50 shown in Table 2-1 were obtainedby the following reaction.

TABLE 2-1 The Obtained Example Compounds 2 to 50 LC/MS LC/MS Ex- reten-mass am- tion spectro- ple Analysis time metry No. Structure CompoundCondition (min.) (m/z)  2

3-[(1S,2S)-1-[5-(2-ethyl-3- methylpyridin-4-yl)-2-[2- (4-fluoro-3,5-dimethylphenyl)-3-[3-(1- methylindazol-5-yl)-2- oxoimidazol-1-yl]-6,7-dihydro-4H- pyrazolo[4,3-c]pyridine-5- carbonyl]indol-1-yl]-2-methylcyclopropyl]- 4H-1,2,4-oxadiazol-5-one SMD- TFA05-3 1.15 858 ([M +H]⁺)  3

3-[(1S,2S)-1-[5-(2-ethyl-3- methylpyridin-4-yl)-2-[2- (4-fluoro-3,5-dimethylphenyl)-3-[3-(3- methyl-1,2-benzothiazol-6-yl)-2-oxoimidazol-1-yl]- 6,7-dihydro-4H- pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl-2- methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-one SMD-TFA05-3 1.22 875 ([M + H]⁺)  4

3-[(1S,2S)-1-[5-(2-ethyl-3- methylpyridin-4-yl)-2-[2- (4-fluoro-3,5-dimethylphenyl)-3-[3-(3- fluoro-4-methoxyphenyl)-2-oxoimidazol-1-yl]-6,7- dihydro-4H- pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl-2- methylcyclopropyl]- 4H-1,2,4-oxadiazol-5-one SMD-TFA05-3 1.21 852 ([M + H]⁺)  5

3-[(1S,2S)-1-[2-[3-[3-(1,3- dimethylindazol-6-yl)-2-oxoimidazol-1-yl]-2-(4- fluoro-3,5-dimethylphenyl)- 6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5- carbonyl]-5-(2-ethyl-3-methylpyridin-4-yl)indol-1- yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one SMD- TFA05-3 1.18 872 ([M + H]⁺)  6

3-[(1S,2S)-1-[2-[2-(4- fluoro-3,5- dimethylphenyl)-3-[3-[1-(2-hydroxy-2- methylpropyl)indazol-5-yl]- 2-oxoimidazol-1-yl]-6,7-dihydro-4H- pyrazolo[4,3-c]pyridine-5- carbonyl]-5-(2-methoxy-3-methylpyridin-4-yl)indol-1- yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one SMD- TFA05-2 1.40 919 ([M + H]⁺)  7

3-[(1S,2S)-1-[5-(2,2- dimethylmorpholin-4-yl)- 2-[2-(4-fluoro-3,5-dimethylphenyl)-3-[3-[1- (2-methoxyethyl)indazol-5-yl]-2-oxoimidazol-1-yl]- 6,7-dihydro-4H- pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2- methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-oneSMD- TFA05-3 1.32 896 ([M + H]⁺)  8

3-[(1S,2S)-1-[2-[2-(4- fluoro-3,5- dimethylphenyl)-3-[2-oxo-3-[1-[(3R)-oxolan-3- yl]indazol-5-yl]imidazol- 1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5- carbonyl]-5-(oxan-4- yl)indol-1-yl]-2-methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-one SMD- TFA05-2 1.38 879 ([M +H]⁺)  9

N-[4-[3-[2-(4-fluoro-3,5- dimethylphenyl)-5-[1- [(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3- yl)cyclopropyl]-5-(oxan-4-yl)indole-2-carbonyl]-6,7- dihydro-4H-pyrazolo[4,3- c]pyridin-3-yl]-2-oxoimidazol-1-yl]-2- methoxyphenyl]-N-(3- methoxypropyl)acetamide SMD-TFA05-2 1.33 929 ([M + H]⁺) 10

3-[(1S,2S)-1-[2-[2-(4- fluoro-3,5-dimethylphenyl)- 3-[2-oxo-3-[1-(2,2,2-trifluoroethyl)indazol-5- yl]imidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3- c]pyridine-5-carbonyl]-5-(oxan-4-yl)indol-1-yl]-2- methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-oneSMD- TFA05-2 1.47 891 ([M + H]⁺) 11

3-[(1S,2S)-1-[2-[(4S)-2-(4- fluoro-3,5-dimethylphenyl)- 3-[3-[1-(2-methoxyethyl)indazol-5-yl]- 2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H- pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(2-methoxy-3- methylpyridin-4-yl)indol-1-yl]-2-methylcyclopropyl]- 4H-1,2,4-oxadiazol-5-one SMD- TFA05-2 1.49 919([M + H]⁺) 12

3-[(1S,2S)-1-[2-[(4S)-2-(4- fluoro-3,5-dimethylphenyl)-4-methyl-3-[3-(1- methylindazol-5-yl)-2- oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3- c]pyridine-5-carbonyl]-5- (2-methoxy-3-methylpyridin-4-yl)indol- 1-yl]-2- methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one SMD- TFA05-1 1.45 874 ([M + H]⁺) 13

3-[(1S,2S)-1-[2-[(4S)-2-(4- fluoro-3,5-dimethylphenyl)-3-[3-[1-(2-hydroxy-2- methylpropyl)indazol-5-yl]- 2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H- pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(2-methoxy-3- methylpyridin-4-yl)indol-1-yl]-2-methylcyclopropyl]- 4H-1,2,4-oxadiazol-5-one SMD- TFA05-1 1.42 932([M + H]⁺) 14

3-[(1S,2S)-1-[2-[(4S)-2-(4- fluoro-3,5-dimethylphenyl)-4-methyl-3-[2-oxo-3-[1- [(3S)-oxolan-3-yl]indazol-5-yl]imidazol-1-yl]-6,7- dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5- (3-fluoro-2-methylpyridin- 4-yl)indol-1-yl]-2-methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-one SMD- TFA05-1 1.15 918 ([M +H]⁺) 15

3-[(1S,2S)-1-[5-[2- (dimethylamino)-3- methylpyridin-4-yl]-2-[(4S)-2-(4-fluoro-3,5- dimethylphenyl)-4-methyl-3-[3-(1-methylindazol-5- yl)-2-oxoimidazol-1-yl]- 6,7-dihydro-4H-pyrazolo[4,3-c]pyridine- 5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-one SQD- FA05-1 0.75 887 ([M +H]⁺) 16

3-[(1S,2S)-1-[2-[(4S)-2-(4- fluoro-3,5- dimethylphenyl)-3-[3-[1-(2-methoxyethyl)indazol- 5-yl]-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H- pyrazolo[4,3-c]pyridine-5- carbonyl]-5-(oxan-4-yl)indol-1-yl]-2- methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-one SMD-TFA05-2 1.45 882 ([M + H]⁺) 17

3-[(1S,2S)-1-[2-[(4S)-2-(4- fluoro-3,5-dimethylphenyl)-4-methyl-3-[3-[1-[(3- methyloxetan-3- yl)methyl]indazol-5-yl]-2-oxoimidazol-1-yl]-6,7- dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5- (oxan-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-one SMD- TFA05-2 1.45 908 ([M +H]⁺) 18

3-[(1S,2S)-1-[2-[(4S)-2-(4- fluoro-3,5-dimethylphenyl)-4-methyl-3-[3-(3-methyl- 1,2-benzothiazol-6-yl)-2-oxoimidazol-1-yl]-6,7- dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5- (oxan-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-one SMD- TFA05-1 1.50 854 ([M +H]⁺) 19

3-[(1S,2S)-1-[2-[(4S)-2-(4- fluoro-3,5-dimethylphenyl)-3-[3-[4-(2-hydroxyethoxy)- 3-methylphenyl]-2- oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H- pyrazolo[4,3-c]pyridine-5- carbonyl]-5-(oxan-4-yl)indol-1-yl]-2- methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-one SMD-TFA05-1 1.36 857 ([M + H]⁺) 20

3-[(1S,2S)-1-[2-[(4S)-2-(4- fluoro-3,5-dimethylphenyl)-3-[3-[4-(1-hydroxy-2- methylpropan-2-yl)oxy-3- methoxyphenyl]-2-oxoimidazol-1-yl]-4- methyl-6,7-dihydro-4H- pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4- yl)indol-1-yl]-2- methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one SMD- TFA05-1 1.40 901 ([M + H]⁺) 21

3-[(1S,2S)-1-[2-[(4S)-3-[3- (4-ethylsulfonylphenyl)-2-oxoimidazol-1-yl]-2-(4- fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydro-4H- pyrazolo[4,3-c]pyridine-5- carbonyl]-5-(oxan-4-yl)indol-1-yl]-2- methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-one SMD-TFA05-1 1.37 875 ([M + H]⁺) 22

3-[(1S,2S)-1-[2-[(4S)-2-(4- fluoro-3,5-dimethylphenyl)-4-methyl-3-[2-oxo-3-[1- [(3S)-oxolan-3-yl]indazol-5-yl]imidazol-1-yl]-6,7- dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5- (oxan-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-one SMD- TFA05-1 1.40 893 ([M +H]⁺) 23

3-[(1S,2S)-1-[2-[(4S)-2-(4- fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1- methylindazol-5-yl)-2- oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H- pyrazolo[4,3-c]pyridine-5- carbonyl]-5-(oxan-4-yl)indol-1-yl]-2- methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-one SMD-TFA05-1 1.41 855 ([M + H]⁺) 24

3-[(1S,2S)-1-[2-[(4S)-3-[3- (1,1-dimethyl-3,4-dihydroisochromen-6-yl)-2- oxoimidazol-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)- 4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5- carbonyl]-5-(oxan-4- yl)indol-1-yl]-2-methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-one SMD- TFA05-1 1.52 867 ([M +H]⁺) 25

3-[(1S,2S)-1-[2-[(4S)-3-[3- [4-[6- (dimethylamino)pyrimidin-4-yl]-3-methylphenyl]-2- oxoimidazol-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)- 4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5- carbonyl]-5-(oxan-4- yl)indol-1-yl]-2-methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-one SMD- TFA05-1 1.12 918 ([M +H]⁺) 26

3-[(1S,2S)-1-[2-[(4S)-2-(4- fluoro-3,5-dimethylphenyl)- 3-[3-[1-(2-fluoroethyl)indazol-5-yl]-2- oxoimidazol-1-yl]-4- methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5- carbonyl]-5-(oxan-4- yl)indol-1-yl]-2-methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-one SMD- TFA05-1 1.39 869 ([M +H]⁺) 27

3-[(1S,2S)-1-[2-[(4S)-2-(4- fluoro-3,5-dimethylphenyl)-3-[3-(6-fluoro-1- methylindazol-5-yl)-2- oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H- pyrazolo[4,3-c]pyridine-5- carbonyl]-5-(oxan-4-yl)indol-1-yl]-2- methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-one SMD-TFA05-1 1.39 855 ([M + H]⁺) 28

3-[(1S,2S)-1-[2-[(4S)-2-(4- fluoro-3,5-dimethylphenyl)-3-[3-[4-fluoro-1-(2,2,2- trifluoroethyl)indazol-5-yl]-2-oxoimidazol-1-yl]-4- methyl-6,7-dihydro-4H- pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4- yl)indol-1-yl]-2- methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one SMD- TFA05-1 1.44 923 ([M + H]⁺) 29

3-[(1S,2S)-1-[2-[(4S)-2-(4- fluoro-3,5-dimethylphenyl)-3-[3-[4-fluoro-1-[(3- methyloxetan-3- yl)methyl]indazol-5-yl]-2-oxoimidazol-1-yl]-4- methyl-6,7-dihydro-4H- pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4- yl)indol-1-yl]-2- methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one SMD- TFA05-1 1.40 925 ([M + H]⁺) 30

3-[(1S,2S)-1-[2-[(4S)-2-(4- fluoro-3,5-dimethylphenyl)-3-[3-[4-fluoro-1-(2- hydroxy-2- methylpropyl)indazol-5-yl]-2-oxoimidazol-1-yl]-4- methyl-6,7-dihydro-4H- pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4- yl)indol-1-yl]-2- methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one SMD- TFA05-1 1.36 913 ([M + H]⁺) 31

3-[(1S,2S)-1-[5-[(4S)-2,2- dimethyloxan-4-yl]-2-[(4S)- 2-(4-fluoro-3,5-dimethylphenyl)-3-[3-[1-(2- methoxyethyl)indazol-5-yl]-2-oxoimidazol-1-yl]-4- methyl-6,7-dihydro-4H- pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2- methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-oneSMD- TFA05-2 1.48 909 ([M + H]⁺) 32

3-[(1S,2S)-1-[5-[(4S)-2,2- dimethyloxan-4-yl]-2-[(4S)-3-[3-(1,3-dimethyl-2- oxobenzoimidazol-5-yl)-2- oxoimidazol-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)- 4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5- carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-one SMD- TFA05-1 1.39 895 ([M +H]⁺) 33

3-[(1S,2S)-1-[5-[(4S)-2,2- dimethyloxan-4-yl]-2-[(4S)- 2-(4-fluoro-3,5-dimethylphenyl)-3-[3-[1-(2- methoxyethyl)-3-methyl-2-oxobenzoimidazol-5-yl]-2- oxoimidazol-1-yl]-4- methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5- carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-one SMD- TFA05-1 1.41 939 ([M +H]⁺) 34

3-[(1S,2S)-1-[5-[(4S)-2,2- dimethyloxan-4-yl]-2-[(4S)- 2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(1H- indazol-5-yl)-2- oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H- pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2- methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-oneSMD- TFA05-1 1.37 851 ([M + H]⁺) 35

3-[(1S,2S)-1-[5-[(4S)-2,2- dimethyloxan-4-yl]-2-[(4S)- 2-(4-fluoro-3,5-dimethylphenyl)-3-[3-[4- fluoro-1-(2,2,2- trifluoroethyl)indazol-5-yl]-2-oxoimidazol-1-yl]-4- methyl-6,7-dihydro-4H- pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2- methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-oneSMD- TFA05-1 1.51 951 ([M + H]⁺) 36

3-[(1S,2S)-1-[5-[(4S)-2,2- dimethyloxan-4-yl]-2-[(4S)- 2-(4-fluoro-3,5-dimethylphenyl)-3-[3-[4- fluoro-1-(2- methoxyethyl)indazol-5-yl]-2-oxoimidazol-1-yl]-4- methyl-6,7-dihydro-4H- pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2- methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-oneSMD- TFA05-1 1.46 927 ([M + H]⁺) 37

3-[(1S,2S)-1-[5-[(4S)-2,2- dimethyloxan-4-yl]-2-[(4S)- 2-(4-fluoro-3,5-dimethylphenyl)-3-[3-[4- fluoro-1-[(3-methyloxetan-3-yl)methyl]indazol-5-yl]-2- oxoimidazol-1-yl]-4- methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5- carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-one SMD- TFA05-1 1.46 953 ([M +H]⁺) 38

3-[(1S,2S)-1-[5-[(4S)-2,2- dimethyloxan-4-yl]-2-[(4S)- 2-(4-fluoro-3,5-dimethylphenyl)-3-[3-[4- fluoro-1-(2-hydroxy-2-methylpropyl)indazol-5-yl]- 2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H- pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2- methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-oneSMD- TFA05-1 1.42 941 ([M + H]⁺) 39

3-[(1S,2S)-1-[5-[(4S)-2,2- dimethyloxan-4-yl]-2-[(4S)- 2-(4-fluoro-3,5-dimethylphenyl)-4-methyl- 3-[3-(2-methyl-3-oxo-1,4-dihydroisoquinolin-6-yl)-2- oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3- c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]- 4H-1,2,4-oxadiazol-5-one SMD- TFA05-1 1.33894 ([M + H]⁺) 40

3-[(1S,2S)-1-[5-[(4S)-2,2- dimethyloxan-4-yl]-2-[(4S)- 2-(4-fluoro-3,5-dimethylphenyl)-3-[3-[4- fluoro-1-[(3S)-oxolan-3- yl]indazol-5-yl]-2-oxoimidazol-1-yl]-4- methyl-6,7-dihydro-4H- pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2- methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-oneSMD- TFA05-1 1.46 939 ([M + H]⁺) 41

3-[(1S,2S)-1-[2-[(4S)-2-(4- fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1- methylindazol-5-yl)-2- oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H- pyrazolo[4,3-c]pyridine-5-carbonyl]-5-[(2S,4S)-2- methyloxan-4-yl]indol-1-yl]-2-methylcyclopropyl]- 4H-1,2,4-oxadiazol-5-one SMD- TFA05-1 1.44 869([M + H]⁺) 42

3-[(1S,2S)-1-[2-[(4S)-2-(4- chloro-3,5-dimethylphenyl)-3-[3-[4-fluoro-1-(2,2,2- trifluoroethyl)indazol-5-yl]-2-oxoimidazol-1-yl]-4- methyl-6,7-dihydro-4H- pyrazolo[4,3-c]pyridine-5-carbonyl]-5-[(4S)-2,2- dimethyloxan-4-yl]indol-1-yl]-2-methylcyclopropyl]- 4H-1,2,4-oxadiazol-5-one SMD- TFA05-1 1.56 967([M + H]⁺) 43

3-[(1S,2S)-1-[2-[(4S)-2-(4- chloro-3,5-dimethylphenyl)-3-[3-[4-fluoro-1-(2- methoxyethyl)indazol-5-yl]- 2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H- pyrazolo[4,3-c]pyridine-5- carbonyl]-5-[(4S)-2,2-dimethyloxan-4-yl]indol-1- yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one SMD- TFA05-1 1.53 943 ([M + H]⁺) 44

3-[(1S,2S)-1-[2-[(4S)-2-(4- chloro-3,5-dimethylphenyl)-3-[3-[4-fluoro-1-(2,2,2- trifluoroethyl)indazol-5-yl]-2-oxoimidazol-1-yl]-4- methyl-6,7-dihydro-4H- pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4- yl)indol-1-yl]-2- methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one SMD- TFA05-1 1.50 939 ([M + H]⁺) 45

3-[(1S,2S)-1-[2-[(4S)-2-(4- chloro-3,5-dimethylphenyl)-3-[3-[4-fluoro-1-(2- methoxyethyl)indazol-5-yl]- 2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H- pyrazolo[4,3-c]pyridine-5- carbonyl]-5-(oxan-4-yl)indol-1-yl]-2- methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-one SMD-TFA05-1 1.46 915 ([M + H]⁺) 46

3-[(1S,2S)-1-[2-[(4S)-2-(4- fluoro-3-methylphenyl)-3-[3-[4-fluoro-1-(2,2,2- trifluoroethyl)indazol-5-yl]-2-oxoimidazol-1-yl]-4- methyl-6,7-dihydro-4H- pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4- yl)indol-1-yl]-2- methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one SMD- TFA05-1 1.39 909 ([M + H]⁺) 47

3-[(1S,2S)-1-[2-[(4S)-3-[3- [4-fluoro-1-(2- methoxyethyl)indazol-5-yl]-2-oxoimidazol-1-yl]-2-(4- fluoro-3-methylphenyl)-4-methyl-6,7-dihydro-4H- pyrazolo[4,3-c]pyridine-5- carbonyl]-5-(oxan-4-yl)indol-1-yl]-2- methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-one SMD-TFA05-1 1.34 885 ([M + H]⁺) 48

3-[(1S,2S)-1-[5-[(4S)-2,2- dimethyloxan-4-yl]-2-[(4S)-3-[3-[4-fluoro-1-(2- methoxyethyl)indazol-5-yl]-2-oxoimidazol-1-yl]-2-(4- fluoro-3-methylphenyl)-4-methyl-6,7-dihydro-4H- pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2- methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-oneSMD- TFA05-1 1.41 913 ([M + H]⁺) 49

3-[(1S,2S)-1-[2-[(4S)-3-[3- (4-chloro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]- 2-(4-fluoro-3- methylphenyl)-4-methyl-6,7-dihydro-4H- pyrazolo[4,3-c]pyridine-5- carbonyl]-5-[(4S)-2,2-dimethyloxan-4-yl]indol-1- yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one SMD- TFA05-1 1.42 885 ([M + H]⁺) 50

3-[(1S,2S)-1-[5-[(4S)-2,2- dimethyloxan-4-yl]-2-[(4S)- 2-(4-fluoro-3-methylphenyl)-4-methyl-3- [3-(1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7- dihydro-4H- pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2- methylcyclopropyl]- 4H-1,2,4-oxadiazol-5-oneSMD- TFA05-1 1.37 851 ([M + H]⁺)

The compounds in Table 2-1 have rotational isomers, and by way ofexample, the ¹H-NMR of Example 2 compound is shown below.

Rotational Isomer A

¹H-NMR (600 MHz, CDCl₃) δ: 11.29 (1H, s), 8.40 (1H, d, J=5.2 Hz), 7.93(1H, s), 7.74 (1H, d, J=1.5 Hz), 7.70 (1H, d, J=8.6 Hz), 7.56 (1H, s),7.45 (1H, dd, J=9.0, 1.5 Hz), 7.38 (1H, d, J=9.0 Hz), 7.28 (1H, m), 7.14(1H, d, J=5.2 Hz), 7.04 (2H, d, J_(HF)=5.9 Hz), 6.82 (1H, s), 6.59 (1H,d, J=3.0 Hz), 6.08 (1H, d, J=3.0 Hz), 4.96 (1H, d, J=16.0 Hz), 4.92 (1H,d, J=16.0 Hz), 4.69 (1H, ddd, J=13.1, 4.4, 4.4 Hz), 4.06 (3H, s), 3.75(1H, ddd, J=13.1, 9.5, 5.0 Hz), 3.07 (2H, m), 2.97 (2H, q, J=7.6 Hz),2.26 (3H, s), 2.25 (6H, s), 1.88 (1H, s), 1.51 (2H, m), 1.37 (3H, t,J=7.6 Hz), 1.17 (3H, d, J=5.6 Hz).

Rotational Isomer B

¹H-NMR (600 MHz, CDCl₃) δ: 11.29 (1H, s), 8.44 (1H, d, J=5.2 Hz), 8.04(1H, s), 7.90 (1H, d, J=1.4 Hz), 7.73 (1H, d, J=8.8 Hz), 7.63 (1H, dd,J=9.0, 1.4 Hz), 7.60 (1H, s), 7.51 (1H, d, J=9.0 Hz), 7.30 (1H, m), 7.20(1H, d, J=5.2 Hz), 7.11 (2H, d, J_(HF)=6.0 Hz), 6.81 (1H, s), 6.71 (1H,d, J=3.0 Hz), 6.22 (1H, d, J=3.0 Hz), 5.24 (1H, d, J=16.3 Hz), 4.64 (1H,d, J=16.3 Hz), 4.45 (1H, ddd, J=13.5, 4.6, 4.0 Hz), 4.12 (3H, s), 3.87(1H, ddd, J=13.5, 10.2, 3.8 Hz), 3.17 (1H, ddd, J=15.5, 10.2, 4.6 Hz),3.02 (1H, m), 3.00 (2H, q, J=7.6 Hz), 2.30 (3H, s), 2.28 (6H, s), 1.96(1H, dd, J=6.0 Hz), 1.64 (1H, m), 1.58 (1H, dd, J=9.4, 6.0 Hz), 1.39(3H, t, J=7.6 Hz), 1.19 (3H, d, J=6.1 Hz).

TABLE 2-2 2-Oxoimidazole compound that was used LC/MS LC/MS retentionmass Analysis time spectro- Example No. 2-Oxoimidazole compound CompoundCondition (min.) metry (m/z) 2-5 (Compound 2g)

3-[(1S,2S)-1-[5-(2-ethyl-3- methylpyridin-4-yl)-2-[2- (4-fluoro-3,5-dimethylphenyl)-3-(2-oxo- 1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3- c]pyridine-5- carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-one SMD- FA05-3 0.86 728 ([M +H]⁺) 6 (Compound 6i)

3-[(1S,2S)-1-[2-[2-(4- fluoro-3,5- dimethylphenyl)-3-(2-oxo-1H-imidazol-3-yl)-6,7- dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5- (2-methoxy-3- methylpyridin-4-yl)indol-1-yl]-2- methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-one SMD- FA05-2 1.33730 ([M + H]⁺) 7 (Compound 7c)

3-[(1S,2S)-1-[5-(2,2- dimethylmorpholin-4-yl)-2- [2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo- 1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3- c]pyridine-5- carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-one SMD- FA05-3 1.22 722 ([M +H]⁺) 8-10 (Compound 8c)

3-[(1S,2S)-1-[2-[2-(4- fluoro-3,5- dimethylphenyl)-3-(2-oxo-1H-imidazol-3-yl)-6,7- dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5- (oxan-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-one SMD- FA05-1 1.19 693 ([M +H]⁺) 11-13 (Compound 11m)

3-[(1S,2S)-1-[2-[(4S)-2-(4- fluoro-3,5- dimethylphenyl)-4-methyl-3-(2-oxo-1H-imidazol-3- yl)-6,7-dihydro-4H- pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(2-methoxy-3- methylpyridin-4-yl)indol- 1-yl]-2-methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-one SMD- FA05-1 1.33 744 ([M +H]⁺) 14 (Compound 14d)

3-[(1S,2S)-1-[2-[(4S)-2-(4- fluoro-3,5- dimethylphenyl)-4-methyl-3-(2-oxo-1H-imidazol-3- yl)-6,7-dihydro-4H- pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(3-fluoro-2- methylpyridin-4-yl)indol- 1-yl]-2-methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-one SMD- FA05-1 1.15 732 ([M +H]⁺) 15 (Compound 15d)

3-[(1S,2S)-1-[5-[2- (dimethylamino)-3- methylpyridin-4-yl]-2-[(4S)-2-(4-fluoro-3,5- dimethylphenyl)-4-methyl- 3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H- pyrazolo[4,3-c]pyridine-5- carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-one SQD- FA05-1 0.67 757 ([M +H]⁺) 16-30 (Compound 16a)

3-[(1S,2S)-1-[2-[(4S)-2-(4- fluoro-3,5- dimethylphenyl)-4-methyl-3-(2-oxo-1H-imidazol-3- yl)-6,7-dihydro-4H- pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4- yl)indol-1-yl]-2- methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one SMD- FA05-1 1.21 707 ([M + H]⁺) 31-40 (Compound31l)

3-[(1S,2S)-1-[5-[(4S)-2,2- dimethyloxan-4-yl]-2- [(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl- 3-(2-oxo-1H-imidazol-3- yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5- carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-one SMD- FA05-1 1.29 735 ([M +H]⁺) 41 (Compound 41f)

3-[(1S,2S)-1-[2-[(4S)-2-(4- fluoro-3,5- dimethylphenyl)-4-methyl-3-(2-oxo-1H-imidazol-3- yl)-6,7-dihydro-4H- pyrazolo[4,3-c]pyridine-5-carbonyl]-5-[(2S,4S)-2- methyloxan-4-yl]indol-1-yl]-2-methylcyclopropyl]- 4H-1,2,4-oxadiazol-5-one SQD- FA05-1 0.96 722([M + H]⁺) 42-43 (Compound 42g)

3-[(1S,2S)-1-[2-[(4S)-2-(4- chloro-3,5- dimethylphenyl)-4-methyl-3-(2-oxo-1H-imidazol-3- yl)-6,7-dihydro-4H- pyrazolo[4,3-c]pyridine-5-carbonyl]-5-[(4S)-2,2- dimethyloxan-4-yl]indol-1-yl]-2-methylcyclopropyl]- 4H-1,2,4-oxadiazol-5-one SMD- FA05-1 1.34 751([M + H]⁺) 44-45 (Compound 44a)

3-[(1S,2S)-1-[2-[(4S)-2-(4- chloro-3,5- dimethylphenyl)-4-methyl-3-(2-oxo-1H-imidazol-3- yl)-6,7-dihydro-4H- pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4- yl)indol-1-yl]-2- methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one SMD- FA05-1 1.27 723 ([M + H]⁺) 46-47 (Compound46f)

3-[(1S,2S)-1-[2-[(4S)-2-(4- fluoro-3-methylphenyl)-4-methyl-3-(2-oxo-1H- imidazol-3-yl)-6,7- dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5- (oxan-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-one SMD- FA05-1 1.16 693 ([M +H]⁺) 48-50 (Compound 48a)

3-[(1S,2S)-1-[5-[(4S)-2,2- dimethyloxan-4-yl]-2- [(4S)-2-(4-fluoro-3-methylphenyl)-4-methyl-3- (2-oxo-1H-imidazol-3-yl)- 6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5- carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-one SMD- FA05-1 1.24 721 ([M +H]⁺)

TABLE 2-3 Halogen compound that was used Example No. Halogen compound  212 15 50

 3 18

 4

 5

 6 13

 7 11 16 31

 8

 9

10

14 22

17

19

20

21

23 41 50

24

25

26

27

28 35 42 44 46

29 37

30 38

32

33

34

36 43 45 47 48

39

40

49

The 2-oxoimidazole compound(3-[(1S,2S)-1-[5-(2-ethyl-3-methylpyridin-4-yl)-2-[2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one,Compound 2g) used in the synthesis of Example Compounds 2 to 5 wassynthesized by the following process.

<Step 2-1>

4-Fluoro-3,5-dimethylaniline hydrochloride (Compound 2b)

4-Fluoro-3,5-dimethylaniline (Compound 2a, 3.97 g, 28.5 mmol) was addedat room temperature while concentrated hydrochloric acid (20 mL) andwater (20 mL) were stirred. The reaction mixture was stirred for 1 h. atthat temperature, then the solid in the reaction mixture was collectedby filtration and dried. To the obtained solid was addedmethoxycyclopentane (20 mL), and the mixture was stirred at 50° C. for 1h., then at room temperature for 1.5 h. The precipitated solid wascollected by filtration and washed with methoxycyclopentane (12 mL). Theobtained solid was dried under reduced pressure to obtain titledCompound 2b (4.88 g, yield 97%) as an off-white solid.

The compound was directly put to use in the next step, <Step 2-2>.

<Step 2-2>

(4-Fluoro-3,5-dimethylphenyl)hydrazine hydrochloride (Compound 2c)

To Compound 2b (1.00 g, 5.69 mmol) obtained in Step 2-1 was addedconcentrated hydrochloric acid (10 mL), and an aqueous solution (2.4 mLof water) of sodium nitrite (511 mg, 7.40 mmol) was added over a periodof 1 min. while the mixture was stirred vigorously at 0° C., then themixture was stirred at 0° C. for 30 min. Then, an aqueous solution (2.4mL of water) of tin(II) chloride (2.27 g, 12.0 mmol) was added over aperiod of 2 min. Further, water (7 mL) was added, and the mixture wasstirred at room temperature for 1 h. The solid in the reaction mixturewas collected by filtration and washed with water (2 mL). Then, it wasdried to obtain the titled Compound 2c (1.75 g, yield 77%, content 48%)as a grey solid.

LC/MS mass spectrometry: m/z 155 ([M+H]⁺).

LC/MS retention time: 0.54 min. (Analysis Condition: SMD-FA05-1).

<Step 2-3>

tert-Butyl3-amino-2-(4-fluoro-3,5-dimethylphenyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate(Compound 2d)

The titled compound was obtained from Compound 1b obtained in Step 1-1and Compound 2c obtained in Step 2-2 by performing an operation similarto Step 1-2 of Example 1 using an appropriate reagent.

LC/MS mass spectrometry: m/z 361 ([M+H]⁺).

LC/MS retention time: 1.04 min. (Analysis Condition: SMD-FA05-3).

<Step 2-4>

tert-Butyl3-(2,2-dimethoxyethylcarbamoylamino)-2-(4-fluoro-3,5-dimethylphenyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate(Compound 2e)

The titled compound was synthesized from Compound 2d obtained in Step2-3 by performing an operation similar to Step 1-3 of Example 1 using anappropriate reagent.

LC/MS mass spectrometry: m/z 492 ([M+H]⁺).

LC/MS retention time: 1.07 min. (Analysis Condition: SMD-FA05-3).

<Step 2-5>

3-[2-(4-Fluoro-3,5-dimethylphenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-1H-imidazol-2-onehydrochloride (Compound 2f)

The titled compound was synthesized from Compound 2e obtained in Step2-4 by performing an operation similar to Step 1-4 of Example 1 using anappropriate reagent.

LC/MS mass spectrometry: m/z 328 ([M+H]⁺).

LC/MS retention time: 0.61 min. (Analysis Condition: SMD-FA05-3).

<Step 2-6>

3-[(1S,2S)-1-[5-(2-Ethyl-3-methylpyridin-4-yl)-2-[2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one(Compound 2g)

The titled compound was synthesized from Compound 2f obtained in Step2-5 and Compound 10 obtained in Step 1-9 by performing an operationsimilar to Step 1-10 of Example 1 using an appropriate reagent.

The 2-oxoimidazole compound(3-[(1S,2S)-1-[2-[2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(2-methoxy-3-methylpyridin-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one,Compound 6i) used in the synthesis of Example Compound 6 was synthesizedby the following process.

<Step 6-1>

5-Bromo-1-(cyanomethyl)-N-methyl-N-phenylindole-2-carboxamide (Compound6c)

The titled compound was synthesized from5-bromo-1-(cyanomethyl)indole-2-carboxylic acid (Compound 6a) andN-methylaniline (Compound 6b) by performing an operation similar to Step1-10 of Example 1 using an appropriate reagent.

LC/MS mass spectrometry: m/z 368 ([M+H]⁺)

LC/MS retention time: 1.25 min. (Analysis Condition: SMID-FA05-3).

<Step 6-2>

5-Bromo-1-[(1S,2S)-1-cyano-2-methylcyclopropyl]-N-methyl-N-phenylindole-2-carboxamide(Compound 6d)

The titled compound was synthesized from Compound 6c obtained in Step6-1 by performing an operation similar to Step 1-6 of Example 1 using anappropriate reagent.

LC/MS retention time: 1.37 min. (Analysis Condition: SMD-FA05-1).

¹H-NMR (400 MHz, DMSO-d₆) δ: 7.69 (1H, s), 7.65-7.25 (7H, m), 6.02 (1H,brs), 3.44 (3H, s), 3.31 (3H, d, J=9.5 Hz), 2.04-1.74 (3H, m).

<Step 6-3>

5-Bromo-N-methyl-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]-N-phenylindole-2-carboxamide(Compound 6e)

The titled compound was synthesized from Compound 6d obtained in Step6-2 by performing an operation similar to Step 1-8 of Example 1 using anappropriate reagent.

LC/MS mass spectrometry: m/z 467 ([M+H]⁺).

LC/MS retention time: 1.33 min. (Analysis Condition: SMD-FA05-01).

<Step 6-4>

5-Bromo-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carboxylicacid (Compound 6f)

A mixture of Compound 6e (9.70 g, 20.8 mmol) obtained in Step 6-3,potassium hydroxide (11.7 g, 208 mmol), and methoxyethanol (41.5 mL) wasstirred at 100° C. for 4 h. 6N Hydrochloric acid (51.9 mL) was addedunder ice cold condition, and the suspension was stirred at roomtemperature for 30 min. The solid was collected by filtration and washedwith water (29.1 mL), then dried under reduced pressure to obtain thetitled Compound 6f (7.42 g, yield 95%) as a light brown solid.

LC/MS mass spectrometry: m/z 376 ([M−H]⁻).

LC/MS retention time: 1.10 min. (Analysis Condition: SMD-FA05-2).

<Step 6-5>

5-(2-Methoxy-3-methylpyridin-4-yl)-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carboxylicacid (Compound 6h)

The DMSO (34.7 mL) suspension of Compound 6f (3.00 g, 7.93 mmol)obtained in Step 6-4, palladium(II) acetate (0.178 g, 0.793 mmol),dicyclohexyl (2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphane(0.756 g, 1.587 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (3.02 g,11.9 mmol), potassium phosphate (10.1 g, 47.6 mmol) was deaerated atroom temperature under reduced pressure, then, nitrogen was introducedin the vessel. Under nitrogen atmosphere, the suspension was stirred at100° C. for 0.5 h., then cooled to room temperature.4-Iodo-2-methoxy-3-methylpyridine (Compound 6g, 1.98 g, 7.93 mmol),water (4.96 mL) were added to the solution, and the solution wassubjected to deaeration under reduced pressure. Nitrogen was introducedin the vessel, and the solution was stirred at 100° C. for 0.5 h. Aftercooling to room temperature, water (12.4 mL) and formic acid (6 mL) wereadded to the solution. After filtration, the filtrate was directlypurified by reversed-phase chromatography (acetonitrile/water, 0.1%formic acid) to obtain the titled Compound 6h (1.83 g, yield 55%).

LC/MS mass spectrometry: m/z 421 ([M+H]⁺).

LC/MS retention time: 1.10 min. (Analysis Condition: SMD-FA05-1).

<Step 6-6>

3-[(1S,2S)-1-[2-[2-(4-Fluoro-3,5-dimethylphenyl)-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(2-methoxy-3-methylpyridin-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one(Compound 6i)

The titled compound was synthesized from Compound 2f obtained in Step2-5 and Compound 6h obtained in Step 6-5 by performing an operationsimilar to Step 1-10 of Example 1 using an appropriate reagent.

The halogen compound (1-(5-bromoindazol-1-yl)-2-methylpropan-2-ol,Compound 61) used in the synthesis of Example Compound 6 was synthesizedby the following process.

<Step 6-7>

1-(5-Bromoindazol-1-yl)-2-methylpropan-2-ol (Compound 6k)

5-Bromoindazole (Compound 6j, 150 mg, 0.761 mmol) and2,2-dimethyloxirane (Compound 6k, 274 mg, 3.81 mmol) were dissolved in1-methylpyrrolidin-2-one (NMP) (1.52 mL), to which potassium carbonate(526 mg, 3.81 mmol) was added. The solution was stirred under microwaveat 180° C. for 30 min. Water was added to the reaction mixture, andextraction was performed using ethyl acetate. The organic layer waswashed with water, and the solvent was removed by evaporation underreduced pressure. The resulting product was purified by silica gelcolumn chromatography (ethyl acetate/hexane=1:1) to obtain the titledCompound 61 (115 mg, yield 56%).

LC/MS mass spectrometry: m/z 269 ([M+H]⁺).

LC/MS retention time: 1.00 min. (Analysis Condition: SMD-FA05-2).

The 2-oxoimidazole reagent(3-[(1S,2S)-1-[5-(2,2-dimethylmorpholin-4-yl)-2-[2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one,Compound 7c) used in the synthesis of Example Compound 7 was synthesizedby the following process.

<Step 7-1>

5-(2,2-Dimethylmorpholin-4-yl)-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carboxylicacid (Compound 7b)

The NMP (44 mL) suspension of 2,2-dimethylmorpholine (Compound 7a, 1.98g, 17.2 mmol), tris (dibenzylideneacetone)dipalladium(0) (0.121 g, 0.132mmol), 2-dicyclohexylphosphino-2′,6′-di-1-propoxy-1,1′-biphenyl (0.123g, 0.264 mmol), sodium tert-butoxide (5.08 g, 529 mmol) was deaerated atroom temperature under reduced pressure, then, nitrogen was introducedin the vessel. Under nitrogen atmosphere, Compound 6f (5.0 g, 13.2 mmol)obtained in Step 6-4 was added to the suspension, and the mixture wasstirred at 100° C. for 0.5 h. then cooled to room temperature. Formicacid was added to the mixture, and the resulting product was directlypurified by reversed-phase chromatography (acetonitrile/water, 0.1%formic acid) to obtain the titled Compound 7b (5.26 g, yield 96%).

LC/MS mass spectrometry: m/z 413 ([M+H]⁺).

LC/MS retention time: 1.00 min. (Analysis Condition: SMD-FA05-1).

<Step 7-2>

3-[(1S,2S)-1-[5-(2,2-Dimethylmorpholin-4-yl)-2-[2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one(Compound 7c)

The titled compound was synthesized from Compound 7b obtained in Step7-1 by performing an operation similar to Step 1-10 of Example 1 usingan appropriate reagent.

The 2-oxoimidazole reagent(3-[(1S,2S)-1-[2-[2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one,Compound 8c) used in the synthesis of Example Compounds 8 to 10 wassynthesized by the following process.

<Step 8-1>

1-[(1S,2S)-2-Methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]-5-(oxan-4-yl)indole-2-carboxylicacid (Compound 8b)

The N,N-dimethylacetamide (DMA) (2.64 mL) suspension of Compound 6f(0.30 g, 0.793 mmol) obtained in Step 6-4, palladium(II) acetate (35.6mg, 0.159 mmol), 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl(0.148 g, 0.317 mmol) was deaerated under reduced pressure, then,nitrogen was introduced in the vessel and the suspension was stirred atroom temperature for 15 min. Under nitrogen atmosphere, a DMA solution(7.9 mL, 7.93 mmol) of 1M (tetrahydro-2H-pyran-4-yl)zinc (II) iodide(Compound 8a) was added, and the mixture was stirred at 80° C. for 15min., and then the mixture was cooled to room temperature. Formic acidwas added to the mixture, and the resulting product was directlypurified by reversed-phase chromatography (methanol/water) to obtain thetitled Compound 8b (0.19 g, yield 61%).

LC/MS mass spectrometry: m/z 382 ([M−H]⁻).

LC/MS retention time: 1.00 min. (Analysis Condition: SMD-FA05-2).

<Step 8-2>

3-[(1S,2S)-1-[2-[2-(4-Fluoro-3,5-dimethylphenyl)-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one(Compound 8c)

The titled compound was synthesized from Compound 8b obtained in Step8-1 by performing an operation similar to Step 1-10 of Example 1 usingan appropriate reagent.

The halogen compound (5-bromo-1-[(3R)-oxolan-3-yl]indazole, Compound 8f)used in the synthesis of Example Compound 8 was synthesized by thefollowing process.

<Step 8-3>

4-Methylbenzenesulfonic acid [(3S)-oxolan-3-yl] (Compound 8e)

To a dichloromethane solution (3.78 mL) of (3S)-oxolan-3-ol (Compound8d, 500 mg, 5.68 mmol) was added pyridine (1.28 mL, 15.9 mmol) and4-methylbenzenesulfonyl chloride (1.51 g, 7.95 mmol) at 0° C. Thesolution was stirred at room temperature, then 15 h. later, water and 1Nhydrochloric acid were added to separate out the organic layer. Theorganic layer was washed sequentially with saturated sodium hydrogencarbonate solution, and brine. The solvent was removed by evaporationunder reduced pressure to obtain the titled Compound 8e (1.36 g, yield99%).

LC/MS retention time: 0.96 min. (Analysis Condition: SMD-FA05-1).

¹H-NMR (400 MHz, CDCl₃) δ: 7.79 (2H, d, J=8 Hz), 7.35 (2H, d, J=8 Hz),5.12 (1H, m), 3.93-3.76 (4H, m), 2.46 (3H, s), 2.13-2.05 (2H, m).

<Step 8-4>

5-Bromo-1-[(3R)-oxolan-3-yl]indazole (Compound 8f)

To a DMF (3.8 mL) solution of 5-bromo-1H-indazole (Compound 6j, 300 mg,1.52 mmol) was added cesium carbonate (992 mg, 3.05 mmol) and Compound8e (369 mg, 1.52 mmol) obtained in Step 8-3, and the mixture was stirredat 100° C. for 2 h. After cooling to room temperature, water was addedto the reaction solution and extraction was performed using ethylacetate. The organic layer was washed with water, and the solvent wasremoved by evaporation under reduced pressure. The resulting product waspurified by silica gel column chromatography (ethyl acetate/hexane=1:1)to obtain the titled Compound 8f (198 mg, yield 49%) as a colorlessoil-like product.

LC/MS mass spectrometry: m/z 267 ([M+H]⁺).

LC/MS retention time: 1.07 min. (Analysis Condition: SMD-FA05-1).

The halogen compound (N-(4-bromo-2-methoxyphenyl)-N-(3-methoxypropyl)acetamide, Compound 9c) used in the synthesis of Example Compound 9 wassynthesized by the following process.

<Step 9-1>

To a DMF (0.8 mL) solution of N-(4-bromo-2-methoxyphenyl)acetamide(Compound 9a, 80 mg, 0.33 mmol) was sequentially added sodium hydride(50 wt % oil dispersion) (18.9 mg, 0.39 mmol) and1-bromo-3-methoxypropane (75 mg, 0.49 mmol), and the resulting mixturewas stirred at room temperature for 12 h. Formic acid was added to thereaction solution, and the resulting product was purified byreversed-phase silica gel chromatography (acetonitrile/water, 0.1%formic acid) to obtain the titled Compound 9c (103 mg, yield 99%) as acolorless gum-like product.

LC/MS mass spectrometry: m/z 316 ([M+H]⁺).

LC/MS retention time: 1.02 min. (Analysis Condition: SMD-FA05-1).

The halogen compound (5-bromo-1-(2,2,2-trifluoroethyl)indazole, Compound10b) used in the synthesis of Example Compound 10 was synthesized by thefollowing process.

<Step 10-1>

The titled compound was synthesized from 2,2,2-trifluoroethyltrifluoromethanesulfonate (Compound 10a) and 5-bromo-1H-indazole(Compound 6j) by performing an operation similar to Step 8-4 of Example8 using an appropriate reagent.

LC/MS mass spectrometry: m/z 279 ([M+H]⁺).

LC/MS retention time: 1.17 min. (Analysis Condition: SMD-FA05-1).

The 2-oxoimidazole reagent(3-[(1S,2S)-1-[2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(2-methoxy-3-methylpyridin-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one,Compound 11m) used in the synthesis of Example Compounds 11 to 13 wassynthesized by the following process.

<Step 11-1>

tert-ButylN-(4-fluoro-3,5-dimethylphenyl)-N-[(2-methylpropan-2-yl)oxycarbonylamino]carbamate(Compound 11b)

5-Bromo-2-fluoro-1,3-dimethylbenzene (Compound 11a, 4.66 g, 22.6 mmol)was dissolved in THF (47.6 mL) and cooled under an external temperatureof −70° C. 1.55M n-Butyl lithium (13.1 mL, 20.4 mmol) was added dropwiseat a temperature of −70° C. or lower and stirred for 1 h. A toluenesolution (25.0 g, 21.7 mmol) of 20 wt % di-tert-butyl azodicarboxylatewas added dropwise at an internal temperature of −40° C. or lower, andthe mixture was stirred for 30 min. Then, the mixture was warmed to roomtemperature over a period of 1 h., and heptane (23.8 mL) and 20%ammonium chloride solution (47.6 mL) were added to perform extraction.The organic layer was concentrated and heptane (7.14 mL) was added tothe concentrated organic layer, and the mixture was heated to anexternal temperature of 70° C. to promote dissolution. Then, thesolution was cooled over a period of 1 h. to induce the precipitation ofcrystals. The crystals were collected by filtration and washed withheptane (2.38 mL). The crystals were dried to obtain a crude product(3.53 g, yield 44%) of the titled Compound 11b.

¹H-NMR (400 MHz, DMSO-D₆) δ:9.64-9.51 (0.8H, m), 9.24-9.07 (0.2H, m),7.09-6.91 (2H, m), 2.29-2.09 (6H, m), 1.53-1.32 (18H, m).

LC/MS retention time: 1.40 min. (Analysis Condition: SMD-FA05-3).

<Steps 11-2, 3, and 4>

tert-Butyl (2S)-3-cyano-2-methyl-4-oxopiperidine-1-carboxylate (Compound11g)

(3S)-3-Aminobutanenitrile hydrochloride (Compound 11c, 10.0 g, 82.9mmol) was dissolved in ethanol (50.0 mL), and triethyl amine (13.9 mL,99.5 mmol) and, to the mixture, ethyl acrylate (10.8 mL, 99.5 mmol) wereadded at room temperature. The solution was stirred at an externaltemperature of 70° C. for 3 h., then cooled to room temperature toobtain a mixture containing ethyl3-[[(2S)-1-cyanopropan-2-yl]amino]propanoate (Compound 11e).

To the reaction solution was added di-tert-butyl dicarbonate (21.7 mL,99.5 mmol) at room temperature. The solution was stirred at roomtemperature for 14 h., then N-methylpiperazine (2.76 mL, 24.9 mmol) wasadded and the mixture was stirred for 4 h. Then, 1N hydrochloric acid(50 mL) was added and extraction was performed using toluene (50 mL).The organic layer was washed with 15% sodium chloride aqueous solution(50.0 mL). The organic layer was concentrated under reduced pressure toobtain a mixture containing ethyl3-[[(2S)-1-cyanopropan-2-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]propanoate(Compound 11f).

To the mixture was added THF (50.0 mL), then potassium tert-butoxide(10.2 g, 91.2 mmol) was added at an internal temperature of 30° C. orlower. Then, the mixture was stirred at room temperature for 1 h. At aninternal temperature of 15° C., 2N hydrochloric acid (82.9 mL, 99.5mmol) was added and extraction was performed using ethyl acetate. Theorganic layer was concentrated after it was washed twice with 15% sodiumchloride aqueous solution (50.0 mL) to obtain the titled Compound 11g(15.8 g, yield 80%).

LC/MS mass spectrometry: m/z 237 ([M−H]⁻).

LC/MS retention time: 0.92 min. (Analysis Condition: SMD-FA05-1).

<Step 11-5>

tert-Butyl(4S)-3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate(Compound 11h)

Compound 11b (2.13 g, 6.01 mmol) obtained in Step 11-1 was dissolved inNMP (6.39 mL), to which methanesulfonic acid (1.30 g, 13.2 mmol) wasadded and the mixture was stirred at an external temperature of 80° C.for 7 h. After the reaction solution was cooled to room temperature,toluene (12.8 mL), potassium carbonate (0.914 g), and water (12.8 g)were added to it, and the reaction solution was stirred at roomtemperature for 10 min. After removing the water layer, a toluene (6.3mL) solution of Compound 11g (1.43 g, 6.01 mmol) obtained in Step 11-4,pyridine hydrochloride (71.0 mg, 0.60 mmol) and toluene (4.2 mL) wereadded and the reaction solution was stirred at an external temperatureof 90° C. for 1 h. The reaction solution was cooled, then washed with 1Msodium hydroxide aqueous solution (12.6 mL). The organic layer wasconcentrated under reduced pressure to synthesize the titled Compound11h (1.68 g, yield 75%).

LC/MS mass spectrometry: m/z 375 ([M+H]⁺).

LC/MS retention time: 1.08 min. (Analysis Condition: SMD-FA05-1).

<Step 11-6>

tert-Butyl(4S)-3-(2,2-dimethoxyethylcarbamoylamino)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate(Compound 11j)

To a DMA (0.53 mL) solution of Compound 11h (106 mg, 0.283 mmol)obtained in Step 11-5 was addedN-(2,2-dimethoxyethyl)imidazole-1-carboxamide (Compound 11i, 62.0 mg,0.311 mol), then potassium tert-butoxide (95.0 mg, 0.849 mol) was addedunder a nitrogen atmosphere, and the mixture was stirred at an externaltemperature of 25° C. for 4 h. Water was added to the reaction solutionand extraction was performed using ethyl acetate. The organic layer waswashed with water, and the solvent was removed by evaporation underreduced pressure. The resulting product was purified by silica gelcolumn chromatography (ethyl acetate/hexane=3:2) to obtain the titledCompound 11j (105 mg, yield 73%).

LC/MS mass spectrometry: m/z 506 ([M+H]⁺).

LC/MS retention time: 1.09 min. (Analysis Condition: SMD-FA05-1).

<Step 11-7>

tert-Butyl(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate(Compound 11k)

Compound 11j (4.45 g, 8.79 mmol) obtained in Step 11-6 was suspended byadding THE (44.5 mL), then methylsulfonic acid (0.676 g, 7.03 mmol) wasadded, and the resulting mixture was stirred at an external temperatureof 60° C. for 2 h. After cooling to room temperature, a solution oftripotassium phosphate (1.87 g, 8.79 mmol) in water (17.8 mL) was added,di-tert-butyl dicarbonate (0.768 g, 3.52 mmol) was added, and theresulting mixture was stirred at room temperature for 1 h. Water wasadded to the reaction solution and extraction was performed using ethylacetate. The organic layer was washed with a saturated sodium chlorideaqueous solution, then dried using magnesium sulfate. After filtration,the organic layer was concentrated under reduced pressure, and purifiedby silica gel column chromatography (ethyl acetate/hexane=3:7) to obtainthe titled Compound 11k (3.43 g, yield 88%).

LC/MS mass spectrometry: m/z 442 ([M+H]⁺).

LC/MS retention time: 1.09 min. (Analysis Condition: SMD-FA05-1).

<Step 11-8>

3-[(4S)-2-(4-Fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-1H-imidazol-2-onehydrochloride (Compound 11l)

To a dichloromethane (8.38 ml) solution of Compound 11k (1.85 g, 4.19mmol) obtained in Step 11-7 was added a 4M hydrogen chloride dioxanesolution (10.5 mL, 41.9 mmol). The mixture was stirred at roomtemperature for 1 h., and the reaction mixture was concentrated underreduced pressure to obtain a crude product (1.63 g) containing thetitled Compound 11l as a brown solid.

LC/MS mass spectrometry: m/z 342 ([M+H]⁺).

LC/MS retention time: 0.63 min. (Analysis Condition: SMD-FA05-1).

<Step 11-9>

3-[(1S,2S)-1-[2-[(4S)-2-(4-Fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(2-methoxy-3-methylpyridin-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one(Compound 11m)

The titled compound was synthesized from Compound 11l obtained in Step11-8 and Compound 6h obtained in Step 6-5 by performing an operationsimilar to Step 1-10 of Example 1 using an appropriate reagent.

The 2-oxoimidazole reagent(3-[(1S,2S)-1-[2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(3-fluoro-2-methylpyridin-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one,Compound 14d) used in the synthesis of Example Compound 14 wassynthesized by the following process.

<Step 14-1>

5-(2-Chloro-3-fluoropyridin-4-yl)-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carboxylicacid (Compound 14b)

The titled compound was synthesized from Compound 6f obtained in Step6-4 and 2-chloro-3-fluoro-4-iodopyridine (Compound 14a) by performing anoperation similar to Step 6-5 of Example 6 using an appropriate reagent.

LC/MS mass spectrometry: m/z 429 ([M+H]⁺).

LC/MS retention time: 1.14 min. (Analysis Condition: SMD-TFA05-3).

<Step 14-2>

5-(3-Fluoro-2-methylpyridin-4-yl)-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carboxylicacid (Compound 14c)

To a mixed suspension of DMSO/water at 7:1 (13.2 mL) containing Compound14b (810 mg, 1.32 mmol) obtained in Step 14-1, 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (48 mg, 0.066mmol), potassium carbonate (2.74 g, 19.8 mmol), methylboronic acid (792mg, 13.2 mmol) was deaerated under reduced pressure at room temperature,then nitrogen was introduced in the vessel. Under a nitrogen atmosphere,the mixture was stirred at 100° C. for 0.5 h, then cooled to roomtemperature. Formic acid was added to the mixture, which was directlypurified by reversed-phase chromatography (acetonitrile/water, 0.1%formic acid) to obtain the titled Compound 14c (124 mg, yield 23%) as apale yellow solid.

LC/MS mass spectrometry: m/z 409 ([M+H]⁺).

LC/MS retention time: 0.85 min. (Analysis Condition: SMD-FA05-3).

<Step 14-3>

3-[(1S,2S)-1-[2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(3-fluoro-2-methylpyridin-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one(Compound 14d)

The titled compound was synthesized from Compound 11l obtained in Step11-8 and Compound 14c obtained in Step 14-2 by performing an operationsimilar to Step 1-10 of Example 1 using an appropriate reagent.

The 2-oxoimidazole reagent(3-[(1S,2S)-1-[5-[2-(dimethylamino)-3-methylpyridin-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one,Compound 15d) used in the synthesis of Example Compound 15 wassynthesized by the following process.

<Step 15-1>

4-Iodo-N,N,3-trimethylpyridine-2-amine (Compound 15b)

A DMF (7.9 mL) solution of 2-chloro-4-iodo-3-methylpyridine (Compound15a, 500 mg, 1.97 mmol), N-ethyl-N-propan-2-ylpropane-2-amine (0.515 mL,2.96 mmol), and a THE solution (2.96 mL, 5.92 mmol) of 2M dimethylaminewas stirred at 130° C. for 17 h., then the solution was cooled to roomtemperature and formic acid (0.4 mL) was added. The solution waspurified by reversed-phase chromatography (acetonitrile/water, 0.1%formic acid) to obtain the titled Compound 15b (258 mg, yield 50%) as alight brown solution.

LC/MS mass spectrometry: m/z 263 ([M+H]⁺).

LC/MS retention time: 0.52 min. (Analysis Condition: SQD-FA05-1).

<Step 15-2>

5-[2-(Dimethylamino)-3-methylpyridin-4-yl]-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carboxylicacid (Compound 15c)

The titled compound was obtained from Compound 6f obtained in Step 6-4and Compound 15b obtained in Step 15-1 by performing an operationsimilar to Step 6-5 of Example 6 using an appropriate reagent.

LC/MS mass spectrometry: m/z 432 ([M−H]⁻).

LC/MS retention time: 0.51 min. (Analysis Condition: SQD-FA05-1).

<Step 15-3>

3-[(1S,2S)-1-[5-[2-(Dimethylamino)-3-methylpyridin-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one(Compound 15d)

The titled compound was synthesized from Compound 15c obtained in Step15-2 and Compound 11l obtained in Step 11-8 by performing an operationsimilar to Step 1-10 of Example 1 using an appropriate reagent.

The 2-oxoimidazole reagent(3-[(1S,2S)-1-[2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one,Compound 16a) used in the synthesis of Example Compounds 16 to 30 wassynthesized by the following process.

<Step 16-1>

3-[(1S,2S)-1-[2-[(4S)-2-(4-Fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one(Compound 16a)

The titled compound was obtained from Compound 11l obtained in Step 11-8and Compound 8b obtained in Step 8-1 by performing an operation similarto Step 1-10 of Example 1 using an appropriate reagent.

The halogen compound (5-bromo-1-[(3-methyloxetan-3-yl)methyl]indazole,Compound 17b) used in the synthesis of Example Compound 17 wassynthesized by the following process.

<Step 17-1>

The titled compound was synthesized from3-methyl-3-[(4-methylphenyl)sulfonylmethyl]oxetane (Compound 17a) and5-bromo-1H-indazole (Compound 6j) by performing an operation similar toStep 9-1 of Example 9 using an appropriate reagent.

LC/MS mass spectrometry: m/z 281 ([M+H]⁺).

LC/MS retention time: 1.10 min. (Analysis Condition: SMD-FA05-2).

The halogen compound (2-(4-bromo-2-methoxyphenoxy)-2-methylpropan-1-ol,Compound 20b) used in the synthesis of Example Compound 20 wassynthesized by the following process.

<Step 20-1>

2-(4-Bromo-2-methoxyphenoxy)-2-methylpropan-1-ol (Compound 20b)

Under a nitrogen atmosphere, a THF solution (0.95M, 4.37 mL, 4.15 mmol)of borane was added dropwise at 0° C. to a THF solution (1.38 mL) of2-(4-bromo-2-methoxyphenoxy)-2-methylpropane carboxylic acid (Compound20a, 400 mg, 1.38 mmol) and the resulting mixture was stirred for 24 h.After 1M sodium hydroxide aqueous solution was added to the mixture andthe mixture was stirred, 1N hydrochloric acid was added forneutralization. Then, ethyl acetate was added to perform extraction. Theorganic layer was washed with water and the solvent was removed byevaporation under reduced pressure to obtain the titled Compound 20b(339 mg, yield 89%).

LC/MS retention time: 1.04 min. (Analysis Condition: SMD-FA05-3).

¹H-NMR (400 MHz, CDCl₃) δ: 7.04-7.01 (2H, m), 6.90-6.86 (1H, m), 3.85(3H, s), 3.44 (2H, m), 3.34 (1H, m), 1.28 (6H, s).

The halogen compound (5-bromo-1-[(3S)-oxolan-3-yl]indazole, Compound22c) used in the synthesis of Example Compound 22 was synthesized by thefollowing process.

<Step 22-1>

(3R)-Oxolan-3-yl 4-methylbenzenesulfonate (Compound 22b)

The titled compound was synthesized by performing an operation similarto Step 8-3 of Example 8 using (3R)-oxolan-3-ol and an appropriatereagent.

LC/MS retention time: 0.95 min. (Analysis Condition: SMD-FA05-3).

<Step 22-2>

5-Bromo-1-[(3S)-oxolan-3-yl]indazole (Compound 22c)

The titled compound was synthesized from Compound 22b obtained in Step22-1 and 5-bromo-1H-indazole by performing an operation similar to Step8-4 of Example 8 using an appropriate reagent.

LC/MS mass spectrometry: m/z 267 ([M+H]⁺).

LC/MS retention time: 1.06 min. (Analysis Condition: SMD-FA05-3).

The halogen compound (6-bromo-1,1-dimethyl-3,4-dihydroisochromene,Compound 24d) used in the synthesis of Example Compound 24 wassynthesized by the following process.

<Step 24-1>

(1,1-Dimethyl-3,4-dihydroisochromen-6-yl) trifluoromethanesulfonate(Compound 24b)

The titled compound was synthesized from1,1-dimethyl-3,4-dihydroisochromen-6-ol (Compound 24a) andtrifluoromethylsulfonyl trifluoromethanesulfonate (triflate anhydride)by performing an operation similar to Step 8-3 of Example 8 using anappropriate reagent.

LC/MS retention time: 0.96 min. (Analysis Condition: SQD-FA05-01).

<Step 24-2>

2-(1,1-Dimethyl-3,4-dihydroisochromen-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(Compound 24c)

After the 1,4-dioxane (2.58 mL) solution of Compound 24b (120 mg, 0.387mmol) obtained in Step 24-1,4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(147 mg, 0.580 mmol), triethyl amine (0.162 mL, 1.16 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (14.2 mg, 0.019 mmol)was deaerated under reduced pressure, nitrogen was introduced in thevessel and the solution was stirred at 100° C. for 14 h. The solutionwas cooled to room temperature, then formic acid was added and theresulting product was purified by reversed-phase chromatography(acetonitrile/water, 0.1% formic acid) to obtain a mixture (134 mg)containing the titled Compound 24c as a light brown liquid.

LC/MS mass spectrometry: m/z 289 ([M+H]⁺).

LC/MS retention time: 1.03 min. (Analysis Condition: SQD-FA05-1).

<Step 24-3>

6-Bromo-1,1-dimethyl-3,4-dihydroisochromene (Compound 24d)

To a methanol (1.9 mL) solution of Compound 24c (111 mg, 0.385 mmol)obtained in Step 24-2, an aqueous solution (1.9 mL) of copper(II)bromide (258 mg, 1.16 mmol) was added and the mixture was stirred at 60°C. for 6 h. After the mixture was cooled to room temperature, asaturated ammonium chloride solution was added, then extraction usingdichloromethane was performed twice, and then the organic layer wasdried with magnesium sulfate. After filtration, the filtrate wasconcentrated under reduced pressure and the residue was purified bysilica gel column chromatography (ethyl acetate/hexane=1:4) to obtainthe titled Compound 24d (47.7 mg, yield 51%) as a colorless liquid.

¹H-NMR (400 MHz, CDCl₃) δ: 7.29 (1H, dd, J=2.0, 8.4 Hz), 7.24-7.22 (1H,m), 6.97 (1H, d, J=8.4 Hz), 3.92 (2H, t, J=5.6 Hz), 2.80 (2H, t, J=5.6Hz), 1.50 (6H, s).

LC/MS retention time: 0.96 min. (Analysis Condition: SQD-FA05-1).

The halogen compound(6-(4-bromo-2-methylphenyl)-N,N-dimethylpyrimidine-4-amine, Compound25b) used in the synthesis of Example Compound 25 was synthesized by thefollowing process.

<Step 25-1>

6-(4-Bromo-2-methylphenyl)-N,N-dimethylpyrimidine-4-amine (Compound 25b)

To a methanol (0.2 mL) solution of4-(4-bromo-2-methylphenyl)-6-chloropyrimidine (Compound 25a, 12.9 mg,0.045 mmol) was added 2M dimethylamine THF solution (0.227 mL, 0.455mmol), and the mixture was stirred at room temperature for 3 h. Thereaction mixture was purified by the reversed-phase silica gel columnchromatography (acetonitrile/water, 0.1% formic acid) to synthesize thetitled Compound 25b (9.2 mg, yield 69%) as an off-white solid.

LC/MS mass spectrometry: m/z 292 ([M+H]⁺).

LC/MS retention time: 0.67 min. (Analysis Condition: SMD-FA05-3).

The halogen compound (5-bromo-4-fluoro-1-(2,2,2-trifluoroethyl)indazole,Compound 28b) used in the synthesis of Example Compound 28 wassynthesized by the following process.

<Step 28-1>

5-Bromo-4-fluoro-1-(2,2,2-trifluoroethyl)indazole (Compound 28b)

The titled compound was synthesized from 2,2,2-trifluoroethyltrifluoromethanesulfonate (Compound 10a) and5-bromo-4-fluoro-1H-indazole (Compound 28a) by performing an operationsimilar to Step 8-4 of Example 8 using an appropriate reagent.

LC/MS mass spectrometry: m/z 297 ([M+H]⁺).

LC/MS retention time: 1.20 min. (Analysis Condition: SMD-FA05-1).

The halogen compound(5-bromo-4-fluoro-1-[(3-methyloxetan-3-yl)methyl]indazole, Compound 29a)used in the synthesis of Example Compound 29 was synthesized by thefollowing process.

<Step 29-1>

5-Bromo-4-fluoro-1-[(3-methyloxetan-3-yl)methyl]indazole (Compound 29a)

The titled compound was synthesized from3-methyl-3-[(4-methylphenyl)sulfonylmethyl]oxetane (Compound 17a) and5-bromo-4-fluoro-1H-indazole (Compound 28a) by performing an operationsimilar to Step 8-4 of Example 8 using an appropriate reagent.

LC/MS mass spectrometry: m/z 299 ([M+H]⁺).

LC/MS retention time: 1.11 min. (Analysis Condition: SMD-FA05-1).

The halogen compound(1-(5-bromo-4-fluoroindazol-1-yl)-2-methylpropan-2-ol, Compound 30a)used in the synthesis of Example Compound 30 was synthesized by thefollowing process.

<Step 30-1>

1-(5-Bromo-4-fluoroindazol-1-yl)-2-methylpropan-2-ol (Compound 30a)

The titled compound was synthesized from 5-bromo-4-fluoro-1H-indazole(Compound 28a) and 2,2-dimethyloxirane (Compound 6k) by performing anoperation similar to Step 6-7 of Example 6 using an appropriate reagent.

LC/MS mass spectrometry: m/z 287 ([M+H]⁺).

LC/MS retention time: 1.01 min. (Analysis Condition: SMD-FA05-1).

The 2-oxoimidazole reagent(3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one,Compound 31l) used in the synthesis of Example Compounds 31 to 40 wassynthesized by the following process.

<Step 31-1>

Ethyl 5-(2,2-dimethyloxan-4-yl)-1H-indole-2-carboxylate (Compound 31c)

Zinc powder (1.95 g, 29.8 mmol) was suspended in DMF (6 mL), and thesuspension was subjected to nitrogen substitution. Chlorotrimethylsilane(0.417 mL, 3.28 mmol), and 1,2-dibromoethane (0.284 mL, 3.28 mmol) wereadded and the resulting mixture was stirred at room temperature for 5min. A DMF (9 mL) solution of 4-iodo-2,2-dimethyltetrahydropyran (5.37g, 22.4 mmol) was added dropwise to the mixture, and the mixture wasstirred at room temperature for 20 min. To this solution were addedpalladium(II) acetate (0.084 g, 0.373 mmol), and4-(N,N-dimethylamino)phenyl]di-tert-butylphosphine (0.198 g, 0.746 mol),ethyl 5-bromoindole-2-carboxylate (2.0 g, 7.46 mmol), and nitrogen wasintroduced in the vessel. The mixture was stirred at an externaltemperature of 50° C. for 1 h., then the external temperature was cooledto 0° C., and 5N hydrochloric acid (6 mL) was added for neutralization.A 30% sodium chloride aqueous solution (50 mL) and ethyl acetate (100mL) were added and the non-dissolved matters were removed with cerite.The filtrate was subjected to extraction using ethyl acetate and theorganic layer was washed with 30% sodium chloride aqueous solution.Then, it was dried with magnesium sulfate and run through a filter, andthe solvent was removed by evaporation under reduced pressure. Theresidue was purified by silica gel column chromatography (ethylacetate/hexane) to synthesize the titled Compound 31c (1.86 g, yield83%) as a pale pink solid.

LC/MS mass spectrometry: m/z 302 ([M+H]⁺).

LC/MS retention time: 0.90 min. (Analysis Condition: SQD-FA05-4).

<Step 31-2>

Ethyl 5-[(4S)-2,2-dimethyloxan-4-yl]-1H-indole-2-carboxylate (Compound31d)

The stereoisomers included in Compound 31c (900 mg) obtained by Step31-1 were separated by supercritical-fluid chromatography to obtain thetitled Compound 31d (423 mg, yield 47%).

Separation Condition

-   -   Device: SFC15 (Waters)    -   Column: CHIRALPAK-IE/SFC, 10×250 mm, 5 μm (Daicel)    -   Column temperature: 40° C.    -   Solvent: Super-critical carbon dioxide/methanol:ethyl acetate        (1:1)=60/40 (Homogenous system)    -   Flow rate: 15 mL/min., 140 bar    -   Analysis Condition    -   Device: Nexera (Shimadzu)    -   Column: CHIRALPAK-IE, 4.6×250 mm, 5 μm (Daicel)    -   Column Temperature: 25° C.    -   Solvent: hexane/ethanol=30/70 (homogenous system)    -   Flow rate: 1 mL/min., room temperature    -   Titled Compound retention time: 9.98 min., isomer retention        time: 6.86 min.

Note that the titled compound was determined to be the S-isomer by X-raycrystallography of Compound 31j.

<Step 31-3>

5-[(4S)-2,2-Dimethyloxan-4-yl]-1H-indole-2-carboxylic acid (Compound31e)

Compound 31d (993 mg, 3.29 mmol) obtained in Step 31-2 was dissolved inmethanol (14.9 mL), and a 2M sodium hydroxide aqueous solution (3.62 mL,7.25 mmol) was added dropwise into the mixture and the mixture wasstirred at an external temperature of 65° C. for 1 h. The reactionsolution was cooled at an external temperature of 15° C., and 5Nhydrochloric acid (1.52 mL, 7.58 mmol) was added dropwise into thereaction solution. Water (7.45 mL) was added dropwise, and theprecipitated solid was collected by filtration. The obtained solid waswashed with water (5.0 mL) and dried under reduced pressure to obtainthe titled Compound 31e (827 mg, yield 96%).

LC/MS mass spectrometry: m/z 274 ([M+H]⁺).

LC/MS retention time: 0.65 min. (Analysis Condition: SQD-FA05-4).

<Step 31-4>

5-[(4S)-2,2-Dimethyloxan-4-yl]-N-methyl-N-phenyl-1H-indole-2-carboxamide(Compound 31f)

Compound 31e (805 mg, 2.95 mmol) obtained in Step 31-3 was dissolved inDMA (8.0 mL), and thionyl chloride (0.256 mL, 3.53 mmol) was addeddropwise into the solution at an internal temperature of 10° C. orlower. After the solution was stirred for an hour, N-methylaniline(0.384 mL, 3.53 mmol) and triethyl amine (0.985 mL, 7.07 mmol) wereadded dropwise at 10° C. or lower, and the solution was stirred at roomtemperature for 1 h. Water (4.0 mL) was added dropwise into thesolution, and the precipitated solid was collected by filtration. Theobtained solid was washed with water (8.0 mL) and dried under reducedpressure to obtain the titled Compound 31f (995 mg, yield 93%).

LC/MS mass spectrometry: m/z 363 ([M+H]⁺).

LC/MS retention time: 1.20 min. (Analysis Condition: SMD-FA05-1).

<Step 31-5>

1-(Cyanomethyl)-5-[(4S)-2,2-dimethyloxan-4-yl]-N-methyl-N-phenylindole-2-carboxamide(Compound 31h)

Compound 31f (101 mg, 0.276 mmol) obtained in Step 31-4 was dissolved in1,3-dimethyl-2-imidazolidinone (DMI) (1.0 mL) at room temperature, and8M potassium hydroxide aqueous solution (0.103 mL, 0.828 mmol) and water(0.10 mL) were added to the solution. To the obtained solution was added2-chloroacetonitrile (0.026 mL, 0.414 mmol) at an external temperatureof 10° C., and the solution was stirred for 2.5 h. 5N Hydrochloric acid(0.193 mL), water (0.10 mL), and cyclopentylmethyl ether (1.0 mL) wereadded to the reaction solution to perform extraction, and the aqueouslayer was subjected to a second extraction using cyclopentylmethyl ether(1.0 mL). The combined organic layer was washed with 15% sodium chloridesolution (1.0 mL), then, the titled Compound 31h was obtained as a lightbrown oil-like product by concentration under a reduced pressure at anexternal temperature of 40° C. and was put to use in the subsequent Step31-6 without being purified.

LC/MS mass spectrometry: m/z 402 ([M+H]⁺).

LC/MS retention time: 0.93 min. (Analysis Condition: SMD-FA05-1).

<Step 31-6>

1-[(1S,2S)-1-Cyano-2-methylcyclopropyl]-5-[(4S)-2,2-dimethyloxan-4-yl]-N-methyl-N-phenylindole-2-carboxamide(Compound 31i)

The titled compound was synthesized from Compound 31h obtained in Step31-5 by performing an operation similar to Step 1-6 of Example 1 usingan appropriate reagent.

LC/MS mass spectrometry: m/z 442 ([M+H]⁺).

LC/MS retention time: 0.95 min. (Analysis Condition: SQD-FA05-1).

<Step 31-7>

5-[(4S)-2,2-Dimethyloxan-4-yl]-N-methyl-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]-N-phenylindole-2-carboxamide(Compound 31i)

The titled compound was synthesized from Compound 311 obtained in Step31-6 by performing an operation similar to Step 1-6 of Example 1 usingan appropriate reagent.

LC/MS mass spectrometry: m/z 501 ([M+H]⁺).

LC/MS retention time: 0.99 min. (Analysis Condition: SQD-FA05-1).

<Step 31-8>

5-[(4S)-2,2-Dimethyloxan-4-yl]-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carboxylicacid (Compound 31k)

The titled compound was synthesized from Compound 31j obtained in Step31-7 by performing an operation similar to Step 6-4 of Example 6 usingan appropriate reagent.

LC/MS mass spectrometry: m/z 401 ([M−H]⁻).

LC/MS retention time: 1.05 min. (Analysis Condition: SMD-FA05-1).

<Step 31-9>

3-[(1S,2S)-1-[5-[(4S)-2,2-Dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one(Compound 31l)

The titled compound was synthesized from Compound 11l obtained in Step11-8 and Compound 31k obtained in Step 31-8 by performing an operationsimilar to Step 1-10 of Example 1 using an appropriate reagent.

The halogen compound5-bromo-1-(2-methoxyethyl)-3-methylbenzoimidazol-2-one (Compound 33b)used in the synthesis of Example Compound 33 was synthesized by thefollowing process.

<Step 33-1>

The titled compound was synthesized from5-bromo-3-methyl-1H-benzoimidazol-2-one (Compound 33a) by performing anoperation similar to Step 8-4 of Example 8 using an appropriate reagent.

LC/MS mass spectrometry: m/z 285 ([M+H]⁺).

LC/MS retention time: 0.95 min. (Analysis Condition: SMD-FA05-1).

The halogen compound (5-bromo-4-fluoro-1-(2-methoxyethyl)indazole,Compound 36a) used in the synthesis of Example Compound 36 wassynthesized by the following process.

<Step 36-1>

The titled compound was synthesized from 5-bromo-4-fluoro-1H-indazole(Compound 28a) by performing an operation similar to Step 8-4 of Example8 using an appropriate reagent.

LC/MS mass spectrometry: m/z 273 ([M+H]⁺).

LC/MS retention time: 1.10 min. (Analysis Condition: SMD-FA05-1).

The halogen compound (5-bromo-4-fluoro-1-[(3S)-oxolan-3-yl]indazole,Compound 40a) used in the synthesis of Example Compound 40 wassynthesized by the following process.

<Step 40-1>

The titled compound was synthesized from 5-bromo-4-fluoro-1H-indazole(Compound 28a) and (3R)-oxolan-3-yl 4-methylbenzenesulfonate (Compound22b) by performing an operation similar to Step 8-4 of Example 8 usingan appropriate reagent.

LC/MS mass spectrometry: m/z 285 ([M+H]⁺).

LC/MS retention time: 1.10 min. (Analysis Condition: SMD-FA05-1).

The 2-oxoimidazole reagent(3-[(1S,2S)-1-[2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-[(2S,4S)-2-methyloxan-4-yl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one,Compound 41f) used in the synthesis of Example Compound 41 wassynthesized by the following process.

<Steps 41-1 and 2>

1-[(1S,2S)-1-Cyano-2-methylcyclopropyl]-N-methyl-5-[(2S,4S)-2-methyloxan-4-yl]-N-phenylindole-2-carboxamide(Compound 41c)

After a DMA (0.12 mL) suspension of zinc (29 mg, 0.44 mmol) wasdeaerated under at room temperature at room temperature, nitrogen wasintroduced in the vessel. Under a nitrogen atmosphere, a 7:5 mixedsolution of chlorotrimethylsilane/1,2-dibromoethane (0.0083 mL, 0.039mmol of chlorotrimethylsilane) was added, and the mixture was stirredfor 15 min., then (2S)-4-iodo-2-methyltetrahydro-2H-pyran (80 mg, 0.35mmol) was added dropwise at room temperature and the mixture was stirredfor 30 min. to obtain a mixture containingiodo-[(2S)-2-methyloxan-4-yl]zinc (Compound 41b). Palladium(II) acetate(6.4 mg, 0.028 mmol), 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl(26 mg, 0.057 mmol),5-bromo-1-[(1S,2S)-1-cyano-2-methylcyclopropyl]-N-methyl-N-phenylindole-2-carboxamide(58 mg, 0.14 mmol), and DMA (0.123 mL) were added, and the mixture wasdeaerated under reduced pressure, then nitrogen was introduced in thevessel and the mixture was stirred for an hour at 80° C. The mixture wascooled to room temperature, to which ethyl acetate and 1N hydrochloricacid were added, and the mixture was filtered. Then, the filtrate wassubjected to extraction using ethyl acetate. The organic layer waswashed once with brine and concentrated under reduced pressure, then,the residue was purified by silica gel column chromatography (ethylacetate/hexane=1:1) to obtain the titled Compound 41c (31 mg, yield51%).

LC/MS mass spectrometry: m/z 428 ([M+H]⁺).

LC/MS retention time: 1.01 min. (Analysis Condition: SQD-AA05-1).

<Step 41-3>

N-Methyl-5-[(2S,4S)-2-methyloxan-4-yl]-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]-N-phenylindole-2-carboxamide(Compound 41d)

The titled compound was synthesized from Compound 41c obtained in Step41-2 by performing an operation similar to Step 1-8 of Example 1 usingan appropriate reagent.

LC/MS mass spectrometry: m/z 487 ([M+H]⁺).

LC/MS retention time: 1.30 min. (Analysis Condition: SMD-FA05-1).

<Step 41-4>

5-[(2S,4S)-2-Methyloxan-4-yl]-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carboxylicacid (Compound 41e)

The titled compound was synthesized from Compound 41d obtained in Step41-3 by performing an operation similar to Step 6-4 of Example 6 usingan appropriate reagent.

LC/MS mass spectrometry: m/z 396 ([M−H]⁻).

LC/MS retention time: 1.02 min. (Analysis Condition: SMD-FA05-1).

<Step 41-5>

3-[(1S,2S)-1-[2-[(4S)-2-(4-Fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-[(2S,4S)-2-methyloxan-4-yl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one(Compound 41f)

The titled compound was synthesized from Compound 41e obtained in Step41-4 by performing an operation similar to Step 1-10 of Example 1 usingan appropriate reagent.

The 2-oxoimidazole reagent(3-[(1S,2S)-1-[2-[(4S)-2-(4-chloro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-[(4S)-2,2-dimethyloxan-4-yl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one,Compound 42g) used in the synthesis of Example Compounds 42 and 43 weresynthesized by the following process.

<Steps 42-1, 2>

tert-Butyl(4S)-3-amino-2-(4-chloro-3,5-dimethylphenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate(Compound 42c)

After (4-chloro-3,5-dimethylphenyl)hydrazine hydrochloride (Compound42b) was obtained from 4-chloro-3,5-dimethylaniline (Compound 42a) byperforming an operation similar to Step 2-2 of Example 2 using anappropriate reagent, Compound 11g obtained in Step 11-4 and anappropriate reagent were used to synthesize Compound 42c by an operationsimilar to Step 1-2 of Example 1.

LC/MS mass spectrometry: m/z 391 ([M+H]⁺).

LC/MS retention time: 1.22 min. (Analysis Condition: SMD-FA10-4).

<Step 42-3>

tert-Butyl(4S)-2-(4-chloro-3,5-dimethylphenyl)-3-(2,2-dimethoxyethylcarbamoylamino)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate(Compound 42d)

The titled compound was synthesized from Compound 42c obtained in Step42-2 by performing an operation similar to Step 1-3 of Example 1 usingan appropriate reagent.

LC/MS mass spectrometry: m/z 522 ([M+H]⁺).

LC/MS retention time: 1.55 min. (Analysis Condition: SMD-TFA05-5).

<Step 42-4>

tert-Butyl(4S)-2-(4-chloro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate(Compound 42e)

The titled compound was synthesized from Compound 42d obtained in Step42-3 by performing an operation similar to Step 11-8 of Example 11 usingan appropriate reagent.

LC/MS mass spectrometry: m/z 458 ([M+H]⁺).

LC/MS retention time: 1.16 min. (Analysis Condition: SMD-FA05-1).

<Step 42-5>

3-[(4S)-2-(4-Chloro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-1H-imidazol-2-onehydrochloride (Compound 42f)

The titled compound was synthesized from Compound 42e obtained in Step42-4 by performing an operation similar to Step 111-8 of Example 11using an appropriate reagent.

LC/MS mass spectrometry: m/z 358 ([M+H]⁺).

LC/MS retention time: 0.69 min. (Analysis Condition: SMD-FA05-1).

<Step 42-6>

3-[(1S,2S)-1-[2-[(4S)-2-(4-chloro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-[(4S)-2,2-dimethyloxan-4-yl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one(Compound 42g)

The titled compound was synthesized from Compound 42f obtained in Step42-5 and Compound 31k obtained in Step 31-8 by performing an operationsimilar to Step 1-10 of Example 1 using an appropriate reagent.

The 2-oxoimidazole reagent(3-[(1S,2S)-1-[2-[(4S)-2-(4-chloro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one,Compound 44a) used in the synthesis of Example Compounds 44 and 45 weresynthesized by the following process.

<Step 44-1>

3-[(1S,2S)-1-[2-[(4S)-2-(4-Chloro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one(Compound 44a)

The titled compound was synthesized from Compound 42f obtained in Step42-5 and Compound 8b obtained in Step 8-1 by performing an operationsimilar to Step 1-10 of Example 1 using an appropriate reagent.

The 2-oxoimidazole reagent(3-[(1S,2S)-1-[2-[(4S)-2-(4-fluoro-3-methylphenyl)-4-methyl-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one,Compound 46f) used in the synthesis of Example Compounds 46 and 47 wassynthesized by the following process.

<Step 46-1>

tert-Butyl(4S)-3-amino-2-(4-fluoro-3-methylphenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate(Compound 46b)

The titled compound was synthesized from(4-fluoro-3-methylphenyl)hydrazine hydrochloride (Compound 46a) andCompound 11g obtained in Step 11-4 by performing an operation similar toStep 1-2 of Example 1 using an appropriate reagent.

LC/MS mass spectrometry: m/z 361 ([M+H]⁺).

LC/MS retention time: 1.02 min. (Analysis Condition: SMD-FA05-1).

<Step 46-2>

tert-Butyl(4S)-3-(2,2-dimethoxyethylcarbamoylamino)-2-(4-fluoro-3-methylphenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate(Compound 46c)

The titled compound was synthesized from Compound 46b obtained in Step46-1 by performing an operation similar to Step 1-3 of Example 1 usingan appropriate reagent.

LC/MS mass spectrometry: m/z 492 ([M+H]⁺).

LC/MS retention time: 1.03 min. (Analysis Condition: SMD-FA05-1).

<Step 46-3>

tert-Butyl(4S)-2-(4-fluoro-3-methylphenyl)-4-methyl-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate(Compound 46d)

The titled compound was synthesized from Compound 46c obtained in Step46-2 by performing an operation similar to Step 11-7 of Example 11 usingan appropriate reagent.

LC/MS mass spectrometry: m/z 428 ([M+H]⁺).

LC/MS retention time: 2.11 min. (Analysis Condition: SMD-FA05-long).

<Step 46-4>

3-[(4S)-2-(4-Fluoro-3-methylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-1H-imidazol-2-onehydrochloride (Compound 46e)

The titled compound was synthesized from Compound 46d obtained in Step46-3 by performing an operation similar to Step 11-8 of Example 11 usingan appropriate reagent.

LC/MS mass spectrometry: m/z 328 ([M+H]⁺).

LC/MS retention time: 0.59 min. (Analysis Condition: SMD-FA05-3).

<Step 46-5>

3-[(1S,2S)-1-[2-[(4S)-2-(4-fluoro-3-methylphenyl)-4-methyl-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one(Compound 46f)

The titled compound was synthesized from Compound 46e obtained in Step46-4 and Compound 8b obtained in Step 8-1 by performing an operationsimilar to Step 1-10 of Example 1 using an appropriate reagent.

The 2-oxoimidazole reagent(3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3-methylphenyl)-4-methyl-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one,Compound 48a) used in the synthesis of Example Compounds 48 to 50 wassynthesized by the following process.

<Step 48-1>

3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3-methylphenyl)-4-methyl-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one(Compound 48a)

The titled compound was synthesized from Compound 46e obtained in Step46-5 and Compound 31k obtained in Step 31-8 by performing an operationsimilar to Step 1-10 of Example 1 using an appropriate reagent.

Examples 51 to 53

An operation similar to Step 7-1 of Example 7 was performed using3-[(1S,2S)-1-[5-bromo-2-[2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one(Compound 51d), substituted morpholine and an appropriate reagent toobtain Example Compounds 51 to 53 shown in Table 2-4 by the followingreaction.

TABLE 2-4 The Obtained Example Compounds 51 to 53 LC/MS LC/MS massretention spectro- Example Analysis time metry No. Structure CompoundCondition (min.) (m/z) 51

3-[(1S,2S)-1-[2-[2-(4- fluoro-3,5- dimethylphenyl)-3-[3-(1-methylindazol-5-yl)-2- oxoimidazol-1-yl[-6,7- dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5- (5-oxa-8- azaspiro[3.5]nonan-8-yl)indol-1-yl]-2- methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-one SMD-TFA05-3 1.31 864 ([M + H]⁺) 52

3-[(1S,2S)-1-[2-[2-(4- fluoro-3,5- dimethylphenyl)-3-[3-(1-methylindazol-5-yl)-2- oxoimidazol-1-yl]-6,7- dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5- (4-oxa-7- azaspiro[2.5loctan-7-yl)indol-1-yl]-2- methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-one SMD-TFA05-3 1.16 850 ([M + H]⁺) 53

3-[(1S,2S)-1-[5-[(2S)-2- ethylmorpholin-4-yl]-2- [2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(1- methylindazol-5-yl)-2- oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3- c]pyridine-5- carbonyl]indol-1-yl]-2-methylcyclopropyl-4H- 1,2,4-oxadiazol-5-one SMD- TFA05-3 1.21 852 ([M +H]⁺)

Compound 51d was synthesized as follows.

<Step 51-1>

tert-Butyl2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate(Compound 51a)

To a dichloromethane (16.8 mL) suspension of Compound 2f (0.611 g, 1.68mmol) obtained in Step 2-5 was added triethyl amine (0.936 mL, 6.72mmol), di-tert-butyl dicarbonate (0.425 mL, 1.85 mmol), and thesuspension was stirred at room temperature for 2 h. Water (20.0 mL) and5% potassium hydrogen sulfate aqueous solution (20.0 mL) were added tothe reaction solution, then extraction was performed usingdichloromethane, and the resulting product was dried using magnesiumsulfate. After filtration, the filtrate was concentrated under reducedpressure and the residue was purified by silica gel columnchromatography (ethyl acetate/hexane=0:1 to 1:0) to obtain the titledCompound 51a (0.360 g, yield 50%).

LC/MS mass spectrometry: m/z 428 ([M+H]⁺).

LC/MS retention time: 1.06 min. (Analysis Condition: SMD-FA05-3).

<Step 51-2>

tert-Butyl2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate(Compound 51b)

The titled compound was synthesized from Compound 51a obtained in Step51-1 and 5-bromo-1-methylindazole by performing an operation similar toStep 1-11 of Example 1 using an appropriate reagent.

LC/MS mass spectrometry: m/z 558 ([M+H]⁺).

LC/MS retention time: 1.25 min. (Analysis Condition: SMD-FA05-1).

<Step 51-3>

1-[2-(4-Fluoro-3,5-dimethylphenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-3-(1-methylindazol-5-yl)imidazol-2-onehydrochloride (Compound 51c)

The titled compound was synthesized from Compound 51b obtained in Step51-2 by performing an operation similar to Step 11-9 of Example 11 usingan appropriate reagent.

LC/MS mass spectrometry: m/z 458 ([M+H]⁺).

LC/MS retention time: 0.78 min. (Analysis Condition: SMD-FA05-1).

<Step 51-4>

3-[(1S,2S)-1-[5-Bromo-2-[2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one(Compound 51d)

The titled compound was synthesized from Compound 51c obtained in Step51-3 and Compound 6f obtained in Step 6-4 by performing an operationsimilar to Step 1-10 of Example 1 using an appropriate reagent.

LC/MS mass spectrometry: m/z 817 ([M+H]^(m)).

LC/MS retention time: 1.41 min. (Analysis Condition: SMD-FA05-1).

Examples 54 to 73

An operation similar to Step 1-10 of Example 1 was performed using anamine derivative and a carboxylic acid derivative to obtain ExampleCompounds 54 to 72 shown in Table 2-5 and Example Compound 73 by thefollowing reaction.

TABLE 2-5 The Obtained Example Compounds 54 to 72 LC/MS LC/MS massretention spectro- Example Analysis time metry No. Structure CompoundCondition (min.) (m/z) 54

3-[(1S,2S)-1-[2-[2-(4- fluoro-3,5- dimethylphenyl)-3-[3-(1-methylindazol-5-yl)-2- oxoimidazol-1-yl]-6,7- dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5- (oxan-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-one SMD- TFA05-3 1.41 823 55

3-[(1S,2S)-1-[2-[2-(4- chloro-3,5- dimethylphenyl)-3-[3-(1-methylindazol-5-yl)-2- oxoimidazol-1-yl]-6,7- dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5- (oxan-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-one SMD- TFA05-2 1.43 839 56

3-[(1S,2S)-1-[2-[2-(4- fluoro-3,5- dimethylphenyl)-3-[3-[1-(2-methoxyethyl)indazol- 5-yl]-2-oxoimidazol-1-yl]- 6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5- carbonyl]-5-(oxan-4-yl)pyrrolo[2,3-b]pyridin- 1-yl]-2- methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one SMD- TFA05-2 1.23 868 57

N-[4-[3-[(4S)-2-(4-fluoro- 3,5-dimethylphenyl)-4-methyl-5-[1-[(1S,2S)-2- methyl-1-(5-oxo-4H- 1,2,4-oxadiazol-3-yl)cyclopropyl]-5-(oxan- 4-yl)indole-2-carbonyl]- 6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3- yl]-2-oxoimidazol-1- yl]cuban-1-yl]-N-(2-methoxyethyl)acetamide SMD- TFA05-1 1.34 924 58

3-[(1S,2S)-1-[5-(2,2- dimethylmorpholin-4-yl)- 2-[2-(4-fluoro-3-methylphenyl)-3-[3-[1-(2- methoxyethyl)indazol-5-yl]-2-oxoimidazol-1-yl]- 6,7-dihydro-4H- pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2- methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-oneSMD- TFA05-3 1.29 883 59

3-[(1S,2S)-1-[5-[(4S)-2,2- dimethyloxan-4-yl]-2-[2- (4-fluoro-3,5-dimethylphenyl)-3-[3-(1- methylindazol-5-yl)-2- oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3- c]pyridine-5- carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-one SMD- TFA05-2 1.44 851 60

3-[1S,2S)-1-[5-[(4S)-2,2- dimethyloxan-4-yl]-2-[2-(3,5-dimethylphenyl)-3- [3-(1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7- dihydro-4H-pyrazolo[4,3- c]pyridine-5-carbonyl]indol-1-yl]-2- methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-oneSMD- TFA05-1 1.41 833 61

3-[(1S,2S)-1-[2-[(4S)-2- (4-fluoro-3,5- dimethylphenyl)-4-methyl-3-[3-(1- methylindazol-5-yl)-2- oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3- c]pyridine-5-carbonyl]-5-[(2S,4S)-2-methyloxan-4 yl]indol-1-yl]-2- methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one SMD- TFA05-1 1.45 851 62

3-[(1S,2S)-1-[2-[(4S)-2- (4-fluoro-3,5- dimethylphenyl)-3-[3-[1-(2-methoxyethyl)indazol- 5-yl]-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H- pyrazolo[4,3-c]pyridine-5-carbonyl]-5-[(2S,4S)-2- methyloxan-4-yl]indol-1-yl]-2-methylcyclopropyl]- 4H-1,2,4-oxadiazol-5-one SMD TFA05-1 1.45 89563

3-[(1S,2S)-1-[7-fluoro-2- [(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-[1- (2-methoxyethyl)indazol-5-yl]-2-oxoimidazol-1-yl]- 4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5- carbonyl]-5-(oxan-4- yl)indol-1-yl]-2-methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-one SMD- TFA05-1 1.38 899 64

3-[(1S,2S)-1-[7-fluoro-2- [(4S)-2-(4-fluoro-3,5- dimethylphenyl)-4-methyl-3-[2-oxo-3-[1- [(3R)-oxolan-3-yl]indazol-5-yl]imidazol-1-yl]-6,7- dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl-5- (oxan-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-one SMD- TFA05-1 1.38 911 65

3-[(1S,2S)-1-[2-[(4S)-2- (4-chloro-3,5- dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5- yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H- pyrazolo[4,3-c]pyridine-5- carbonyl]-5-[(4S)-2,2-dimethyloxan-4-yl]indol- 1-yl]-2- methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one SMD- TFA05-1 1.53 899 66

3-[(1S,2S)-1-[5-[(4S)-2,2- dimethyloxan-4-yl]-2- [(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4- methyl-3-[3-(1- methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7- dihydro-4H-pyrazolo[4,3- c]pyridine-5-carbonyl]indol-1-yl]-2- methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-oneSMD- TFA05-2 1.47 866 67

3-[(1S,2S)-1-[5-[(4S)-2,2- dimethyloxan-4-yl]-2- [(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4- fluoro-l-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4- methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5- carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-one SMD- TFA05-1 1.46 883 68

3-[(1S,2S)-1-[2-[(4S)-3- [3-(4-chloro-1- methylindazol-5-yl)-2-oxoimidazol-1-yl]-2-(4- fluoro-3,5- dimethylphenyl)-4-methyl-6,7-dihydro-4H- pyrazolo[4,3-c]pyridine-5- carbonyl]-5-[(4S)-2,2-dimethyloxan-4-yl]indol- 1-yl]-2- methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one SMD- TFA05-1 1.47 899 69

3-[(1S,2S)-1-[5-[(4S)-2,2- dimethyloxan-4-yl]-2- [(4S)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2- oxoimidazol-1-yl]-2-(4- fluoro-3-methylphenyl)-4-methyl-6,7-dihydro-4H- pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2- methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-oneSMD- TFA05-1 1.40 869 70

3-[(1S,2S)-1-[(4S)-2,2- dimethyloxan-4-yl]-2- [(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(6- fluoro-l-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4- methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5- carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-one SMD- TFA05-1 1.43 883 71

3-[(1S,2S)-1-[5-[(4S)-2,2- dimethyloxan-4-yl]-2- [(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-[6- fluoro-1-(2- methoxyethyl)indazol-5-yl]-2-oxoimidazol-1-yl]-4- methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5- carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-one SMD- TFA05-1 1.44 927 72

3-[(1S,2S)-1-[2-[(4S)-3- [3-(4-chloro-1- methylindazol-5-yl)-2-oxoimidazol-1-yl]-2-(4- fluoro-3,5- dimethylphenyl)-4-methyl-6,7-dihydro-4H- pyrazolo[4,3-c]pyridine-5- carbonyl]-5-(oxan-4-y)indol-1-yl]-2- methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-one SMD-TFA05-1 1.40 871

Note that the compounds in Table 2-5 have rotational isomers, and by wayof example, the ¹H-NMR of Example Compounds 66 and 67 are shown below.

<Example Compound 66>

Main Rotational Isomer

¹H-NMR (600 MHz, CDCl₃) δ: 11.32 (1H, s), 8.04 (1H, d, J=0.4 Hz), 7.86(1H, d, J=1.4 Hz), 7.61 (1H, m), 7.59 (1H, m), 7.52 (1H, s), 7.50 (H, d,J=9.0 Hz), 7.27 (1H, m), 7.15 (2H, d, J_(HF)=6.0 Hz), 6.74 (1H, d, J=3.1Hz), 6.70 (1H, s), 6.32 (1H, d, J=3.1 Hz), 5.79 (1H, q, J=6.6 Hz), 4.47(1H, dd, J=13.6, 5.0 Hz), 4.12 (3H, s), 3.89-3.81 (2H, m), 3.60 (1H,ddd, J=13.6, 13.1, 3.6 Hz), 3.15 (1H, ddd, J=16.0, 13.1, 5.0 Hz),3.09-2.98 (2H, m), 2.27 (6H, d, J_(HF)=1.4 Hz), 1.91 (1H, dd, J=6.0 Hz),1.82-1.60 (4H, m), 1.60-1.50 (2H, m), 1.55 (3H, d, J=6.6 Hz), 1.34 (3H,s), 1.28 (3H, s), 1.19 (3H, d, J=5.9 Hz).

Secondary Rotational Isomer

¹H-NMR (600 MHz, CDCl₃) δ: 11.26 (1H, s), 7.93 (1H, s), 7.65 (1H, s),7.57 (1H, d, J=8.6 Hz), 7.49 (1H, m), 7.34 (2H, s), 7.25 (1H, m), 7.05(2H, d, J_(HF)=6.0 Hz), 6.69 (1H, s), 6.59 (1H, d, J=3.1 Hz), 6.09 (1H,d, J=3.1 Hz), 5.26 (1H, q, J=6.6 Hz), 4.87 (1H, dd, J=12.8, 5.1 Hz),4.07 (3H, s), 3.90-3.78 (2H, m), 3.40 (1H, ddd, J=12.8, 12.6, 4.5 Hz),3.10-2.98 (3H, m), 2.23 (6H, s), 1.82-1.37 (10H, m), 1.33 (3H, s), 1.25(3H, s), 1.06 (3H, d, J=6.2 Hz).

<Example Compound 67>

Main Rotational Isomer

¹H-NMR (600 MHz, CDCl₃) δ: 11.32 (1H, s), 8.13 (1H, d, J_(HF)=0.7 Hz),7.59 (1H, d, J=8.6 Hz), 7.52 (1H, s), 7.48 (1H, dd, J=8.9 Hz, J_(HF)=6.9Hz), 7.28 (1H, d, J=8.9 Hz), 7.26 (1H, dd, J=8.6, 1.7 Hz), 7.16 (2H, d,J_(HF)=6.1 Hz), 6.70 (1H, s), 6.61 (1H, dd, J=3.0 Hz, J_(HF)=1.1 Hz),6.31 (1H, d, J=3.0 Hz), 5.79 (1H, q, J=6.7 Hz), 4.47 (1H, dd, J=13.5,5.2 Hz), 4.12 (3H, s), 3.88 (1H, m), 3.83 (1H, m), 3.60 (1H, ddd,J=13.5, 12.9, 3.6 Hz), 3.15 (1H, ddd, J=15.8, 12.9, 5.2 Hz), 3.04 (1H,m), 3.00 (1H, m), 2.29 (6H, d, J_(HF)=1.1 Hz), 1.91 (1H, dd, J=6.1, 5.8Hz), 1.79-1.76 (2H, m), 1.74 (1H, m), 1.65 (1H, m), 1.57 (3H, d, J=6.7Hz), 1.60-1.55 (1H, m), 1.52 (1H, dd, J=9.5, 5.8 Hz), 1.34 (3H, s), 1.28(3H, s), 1.20 (3H, d, J=6.0 Hz).

Secondary Rotational Isomer

¹H-NMR (600 MHz, CDCl₃) δ: 11.27 (1H, s), 8.04 (1H, s), 7.55 (1H, d,J=8.7 Hz), 7.52 (1H, s), 7.25-7.22 (2H, m), 7.12 (1H, d, J=8.8 Hz), 7.06(2H, d, J_(HF)=6.0 Hz), 6.71 (1H, s), 6.47 (1H, m), 6.08 (1H, d, J=3.0Hz), 5.26 (1H, q, J=6.6 Hz), 4.87 (1H, dd, J=13.1, 4.8 Hz), 4.07 (3H,s), 3.90-3.80 (2H, m), 3.39 (1H, ddd, J=13.1, 12.2, 4.6 Hz), 3.08-2.97(3H, m), 2.25 (6H, s), 1.79-1.73 (3H, m), 1.67 (3H, d, J=6.6 Hz), 1.64(1H, m), 1.45-1.37 (2H, m), 1.34 (3H, s), 1.28 (3H, s), 1.06 (3H, d,J=6.0 Hz).

Compound 55e used in the synthesis of Example Compound 55 wassynthesized as follows.

<Step 55-1>

tert-Butyl3-amino-2-(4-chloro-3,5-dimethylphenyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate(Compound 55a)

The titled compound was synthesized from Compound 42a obtained in Step42-1 and Compound 1b obtained in Step 1-1 by performing an operationsimilar to Step 1-2 of Example 1 using an appropriate reagent.

LC/MS mass spectrometry: m/z 377 ([M+H]⁺).

LC/MS retention time: 0.87 min. (Analysis Condition: SQD-FA05-1).

<Step 55-2>

tert-Butyl2-(4-chloro-3,5-dimethylphenyl)-3-(2,2-dimethoxyethylcarbamoylamino)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate(Compound 55b)

The titled compound was synthesized from Compound 55a obtained in Step55-1 by performing an operation similar to Step 1-3 of Example 1 usingan appropriate reagent.

LC/MS mass spectrometry: m/z 508 ([M+H]⁺).

LC/MS retention time: 0.83 min. (Analysis Condition: SQD-FA05-1).

<Step 55-3>

tert-Butyl2-(4-chloro-3,5-dimethylphenyl)-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate(Compound 55c)

The DMF (7.11 mL) suspension of Compound 55b (903 mg, 1.78 mmol)obtained in Step 55-2 and p-toluenesulfonic acid monohydrate (338 mg,1.78 mmol) was stirred at 80° C. for 1 h. After the suspension wascooled to room temperature, potassium phosphate (377 mg, 1.78 mmol),water (3.5 mL), and di-tert-butyl dicarbonate (388 mg, 1.78 mmol) wereadded and the resulting mixture was stirred at room temperature for 1 h.Water was added to the reaction mixture, and extraction was performedusing ethyl acetate, then the organic layer was washed with brine andthe resulting product was dried with magnesium sulfate anhydride. Afterfiltration, the filtrate was concentrated under reduced pressure and theresidue was purified by silica gel column chromatography (ethylacetate/hexane=1:4 to 1:0) to obtain the titled Compound 55c (799 mg,yield 100%) as a pale yellow foam.

LC/MS mass spectrometry: m/z 444 ([M+H]⁺).

LC/MS retention time: 0.82 min. (Analysis Condition: SQD-FA05-1).

<Step 55-4>

tert-Butyl2-(4-chloro-3,5-dimethylphenyl)-3-[3-(1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate(Compound 55d)

The titled compound was synthesized from Compound 55c obtained in Step55-3 and 5-bromo-1-methylindazole (Compound 1q) by performing anoperation similar to Step 1-11 of Example 1 using an appropriatereagent.

LC/MS mass spectrometry: m/z 574 ([M+H]⁺).

LC/MS retention time: 1.34 min. (Analysis Condition: SMD-FA05-1).

<Step 55-5>

1-[2-(4-Chloro-3,5-dimethylphenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-3-(1-methylindazol-5-yl)imidazol-2-onehydrochloride (Compound 55e)

The titled compound was synthesized from Compound 55d obtained in Step55-4 by performing an operation similar to Step 11-8 of Example 11 usingan appropriate reagent.

LC/MS mass spectrometry: m/z 474 ([M+H]⁺).

LC/MS retention time: 0.81 min. (Analysis Condition: SMD-FA05-1).

Compound 56c used in the synthesis of Example Compound 56 wassynthesized as follows.

<Step 56-1>

tert-Butyl2-(4-fluoro-3,5-dimethylphenyl)-3-[3-[1-(2-methoxyethyl)indazol-5-yl]-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate(Compound 56b)

The titled compound was synthesized from Compound 51a obtained in Step51-1 and 5-bromo-1-(2-methoxyethyl)indazole (Compound 56a) by performingan operation similar to Step 1-11 of Example 1 using an appropriatereagent.

LC/MS mass spectrometry: m/z 602 ([M+H]⁺).

LC/MS retention time: 1.30 min. (Analysis Condition: SMD-FA05-2).

<Step 56-2>

1-[2-(4-Fluoro-3,5-dimethylphenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-3-[1-(2-methoxyethyl)indazol-5-yl]imidazol-2-onehydrochloride (Compound 56c)

The titled compound was synthesized from Compound 56b obtained in Step56-1 by performing an operation similar to Step 11-8 of Example 11 usingan appropriate reagent.

LC/MS mass spectrometry: m/z 502 ([M+H]⁺).

LC/MS retention time: 0.54 min. (Analysis Condition: SQD-FA05-1).

The amine derivative (Compound 57j) used in the synthesis of ExampleCompound 57 was synthesized as follows.

<Step 57-1>

tert-Butyl N-(4-isocyanatocuban-1-yl) carbamate (Compound 57b)

To a toluene (2.1 mL) solution of4-[(2-methylpropan-2-yl)oxycarbonylamino]cubane-1-carboxylic acid(Compound 57a, 111 mg, 0.423 mmol) was added at room temperaturetriethyl amine (0.0676 mL, 0.487 mmol) and diphenylphosphoryl azide(0.10 mL, 0.465 mmol), and the resulting mixture was stirred at roomtemperature for 100 min., then at 85° C. for 3.5 h. The solvent in thereaction mixture was removed by evaporation under reduced pressure, andthe titled Compound 57b was obtained as a crude product.

¹H-NMR (400 MHz, CDCl₃) δ: 12.3 (1H, brs), 3.95 (6H, brs), 1.45 (9H, s).

<Step 57-2>

tert-Butyl(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-[[4-[(2-methylpropan-2-yl)oxycarbonylamino]cuban-1-yl]carbamoylamino]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate(Compound 57c)

The titled compound was synthesized from Compound 57b obtained in Step57-1 and Compound 11h obtained by Step 11-5 by performing an operationsimilar to Step 1-3 of Example 1 using an appropriate reagent.

LC/MS mass spectrometry: m/z 636 ([M+H]⁺).

LC/MS retention time: 0.93 min. (Analysis Condition: SQD-FA05-1).

<Step 57-3>

tert-Butyl(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[5-hydroxy3-[4-[(2-methylpropan-2-yl)oxycarbonylamino]cuban-1-yl]-2-oxoimidazolidin-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate(Compound 57d)

To a DMA (0.25 mL) suspension of Compound 57c (31.6 mg, 0.050 mmol)obtained in Step 57-2 and cesium carbonate (82.8 mg, 0.254 mmol) wereadded at room temperature 1,2-dichloro-1-ethoxyethane (0.0155 mL, 0.127mmol), and the mixture was stirred at room temperature for 170 min.Cesium carbonate (104 mg, 0.32 mmol) followed by1,2-dichloro-1-ethoxyethane (0.0184 mL, 0.162 mmol) were added to thereaction mixture at room temperature, and the resulting mixture wasstirred at room temperature for 16 h. The reaction mixture was dilutedwith ethyl acetate and water, then 1N hydrochloric acid (0.54 mL) wasadded to adjust the pH to 7, and then extraction was performed usingethyl acetate. The organic layer was dried using magnesium sulfate, thenthe solvent was removed by evaporation under reduced pressure, and thentoluene was added and the solvent was removed by evaporation underreduced pressure to obtain the titled Compound 57d as a crude product.

LC/MS mass spectrometry: m/z 678 ([M+H]⁺).

LC/MS retention time: 0.98 min. (Analysis Condition: SQD-FA05-1).

<Step 57-4>

tert-Butyl(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-[3-[4-[(2-methylpropan-2-yl)oxycarbonylamino]cuban-1-yl]-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate(Compound 57e)

To a THF (1.1 mL) solution of Compound 57d (115 mg, 0.17 mmol) obtainedin Step 57-3 was added at room temperature methylsulfonic acid (0.011mL, 0.17 mmol), then the mixture was stirred at 60° C. for 90 min.Potassium phosphate (36.5 mg, 0.172 mmol), water (0.45 mL) and(2-methylpropan-2-yl)oxycarbonyl tert-butyl carbonate (0.012 mL, 0.052mmol) were added to the reaction mixture, and the resulting mixture wasstirred for 1 h. Then, after the reaction mixture was diluted withdichloromethane, it was washed with water. The organic layer was driedusing magnesium sulfate, and the solvent was removed by evaporationunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane=1:2 to 1:1) to obtain the titledCompound 57e (48.5 mg, yield 43%).

LC/MS mass spectrometry: m/z 660 ([M+H]⁺).

LC/MS retention time: 1.04 min. (Analysis Condition: SQD-FA05-1).

<Step 57-5>

tert-Butyl(4S)-3-[3-[4-[acetyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]cuban-1-yl]-2-oxoimidazol-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate(Compound 57f)

To a THF (0.22 mL) solution of Compound 57e (16.1 mg, 0.024 mmol)obtained in Step 57-4 was added at −26° C., a 1.7M potassium pentoxidetoluene solution (0.024 mL, 0.041 mmol), and the mixture was stirred at−30° C. for 3 min. Acetic anhydride (8 μL, 0.085 mmol) was added to thereaction mixture at −30° C., and the mixture was stirred at atemperature of −30° C. to −25° C. for 5 min. and at a temperature of−25° C. to room temperature for 3 min. After water (0.5 mL) was added tothe reaction mixture, the mixture was diluted using ethyl acetate, andmore water was added and extraction was performed using ethyl acetate.The organic layer was dried using magnesium sulfate, and the solvent wasremoved by distillation under reduced pressure, then the resultingproduct was purified by silica gel column chromatography (ethylacetate/hexane=1:3 to 2:3) to obtain the titled Compound 57f (9.2 mg,yield 54%).

LC/MS mass spectrometry: m/z 701 ([M+H]⁺).

LC/MS retention time: 1.12 min. (Analysis Condition: SQD-FA05-1).

<Step 57-6>

N-[4-[3-[(4S)-2-(4-Fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-2-oxoimidazol-1-yl]cuban-1-yl]acetamide2,2,2-trifluoroacetate (Compound 57g)

To a dichloromethane (0.097 mL) solution of Compound 57f (8.5 mg, 0.012mmol) obtained in Step 57-5 was added TFA (0.019 mL) at roomtemperature, and the resulting mixture was stirred at room temperaturefor 3 h. After the solvent in the reaction mixture was removed byevaporation under reduced pressure, toluene was added and the solventwas removed by evaporation, and hexane-dichloromethane was added and thesolvent was removed by evaporation to obtain the titled Compound 57g(9.4 mg) as a crude product.

LC/MS mass spectrometry: m/z 501 ([M+H]⁺).

LC/MS retention time: 0.49 min. (Analysis Condition: SQD-FA05-1).

<Step 57-7>

tert-Butyl(4S)-3-[3-(4-acetamidecuban-1-yl)-2-oxoimidazol-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate(Compound 57h)

The titled compound was synthesized from Compound 57g obtained in Step57-6 by performing an operation similar to Step 51-1 of Example 51 usingan appropriate reagent.

LC/MS mass spectrometry: m/z 602 ([M+H]⁺).

LC/MS retention time: 0.85 min. (Analysis Condition: SQD-FA05-1).

<Step 57-8>

tert-Butyl(4S)-3-[3-[4-[acetyl(2-methoxyethyl)amino]cuban-1-yl]-2-oxoimidazol-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate(Compound 57i)

The titled compound was synthesized from Compound 57h obtained in Step57-7 by performing an operation similar to Step 57-5 of Example 57 usingan appropriate reagent.

LC/MS mass spectrometry: m/z 660 ([M+H]⁺).

LC/MS retention time: 0.93 min. (Analysis Condition: SQD-FA05-1).

<Step 57-9>

N-[4-[3-[(4S)-2-(4-Fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-2-oxoimidazol-1-yl]cuban-1-yl]-N-(2-methoxyethyl)acetamide;hydrochloride (Compound 57i)

The titled compound was synthesized from Compound 571 obtained in Step57-8 by performing an operation similar to Step 11-8 of Example 11 usingan appropriate reagent.

LC/MS mass spectrometry: m/z 560 ([M+H]⁺).

LC/MS retention time: 0.53 min. (Analysis Condition: SQD-FA05-1).

Compound 58e used in the synthesis of Example Compound 58 wassynthesized as follows.

<Step 58-1>

tert-Butyl3-amino-2-(4-fluoro-3-methylphenyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate(Compound 58a)

The titled compound was synthesized from Compound 1b obtained in Step1-1 and Compound 46a obtained in Step 46-1 by performing an operationsimilar to Step 1-2 of Example 1 using an appropriate reagent.

LC/MS mass spectrometry: m/z 347 ([M+H]⁺).

LC/MS retention time: 0.98 min. (Analysis Condition: SMD-FA05-3).

<Step 58-2>

tert-Butyl3-(2,2-dimethoxyethylcarbamoylamino)-2-(4-fluoro-3-methylphenyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate(Compound 58b)

The titled compound was synthesized from Compound 58a obtained in Step58-1 by performing an operation similar to Step 1-3 of Example 1 usingan appropriate reagent.

LC/MS mass spectrometry: m/z 478 ([M+H]⁺).

LC/MS retention time: 1.03 min. (Analysis Condition: SMD-FA05-3).

<Step 58-3>

tert-Butyl2-(4-fluoro-3-methylphenyl)-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate(Compound 58c)

The titled compound was synthesized from Compound 58b obtained in Step58-2 by performing an operation similar to Step 11-7 of Example 11 usingan appropriate reagent.

LC/MS mass spectrometry: m/z 414 ([M+H]⁺).

LC/MS retention time: 0.72 min. (Analysis Condition: SQD-FA05-1).

<Step 58-4>

tert-Butyl2-(4-fluoro-3-methylphenyl)-3-[3-[1-(2-methoxyethyl)indazol-5-yl]-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate(Compound 58d)

The titled compound was synthesized from Compound 58c obtained in Step58-3 and 5-bromo-1-(2-methoxyethyl)indazole (Compound 56a) by performingan operation similar to Step 1-11 of Example 1 using an appropriatereagent.

LC/MS mass spectrometry: m/z 588 ([M+H]⁺).

LC/MS retention time: 0.88 min. (Analysis Condition: SQD-FA05-1).

<Step 58-5>

1-[2-(4-Fluoro-3-methylphenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-3-[1-(2-methoxyethyl)indazol-5-yl]imidazol-2-onehydrochloride (Compound 58e)

The titled compound was synthesized from Compound 58d obtained in Step58-4 by performing an operation similar to Step 11-9 of Example 11 usingan appropriate reagent.

LC/MS mass spectrometry: m/z 488 ([M+H]⁺).

LC/MS retention time: 0.50 min. (Analysis Condition: SQD-FA05-1).

Compound 60c used in the synthesis of Example Compound 60 wassynthesized by the following process.

<Step 60-1>

tert-Butyl2-(3,5-dimethylphenyl)-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate(Compound 60a)

The titled compound was synthesized from Compound 1g obtained in Step1-4 by performing an operation similar to Step 51-1 of Example 51 usingan appropriate reagent.

LC/MS mass spectrometry: m/z 410 ([M+H]⁺).

LC/MS retention time: 0.77 min. (Analysis Condition: SQD-FA05-1).

<Step 60-2>

tert-Butyl2-(3,5-dimethylphenyl)-3-[3-(1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate(Compound 60b)

The titled compound was synthesized from Compound 60a obtained in Step60-1 and 5-bromo-1-methylindazole (Compound 1q) by performing anoperation similar to Step 1-11 of Example 1 using an appropriatereagent.

LC/MS mass spectrometry: m/z 540 ([M+H]⁺).

LC/MS retention time: 1.24 min. (Analysis Condition: SMD-FA05-3).

<Step 60-3>

1-[2-(3,5-Dimethylphenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-3-(1-methylindazol-5-yl)imidazol-2-onehydrochloride (Compound 60c)

The titled compound was synthesized from Compound 60b obtained in Step60-2 by performing an operation similar to Step 11-8 of Example 11 usingan appropriate reagent.

LC/MS mass spectrometry: m/z 440 ([M+H]⁺).

LC/MS retention time: 0.74 min. (Analysis Condition: SMD-FA05-2).

Compound 61b used in the synthesis of Example Compound 61 wassynthesized by the following process.

<Step 61-1>

tert-Butyl(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-[3-(1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate(Compound 61a)

The titled compound was synthesized from Compound 11k obtained in Step11-7 and 5-bromo-1-methylindazole (Compound 1q) by performing anoperation similar to Step 1-11 of Example 1 using an appropriatereagent.

LC/MS mass spectrometry: m/z 572 ([M+H]⁺).

LC/MS retention time: 1.30 min. (Analysis Condition: SMD-FA05-1).

<Step 61-2>

1-[(4S)-2-(4-Fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-3-(1-methylindazol-5-yl)imidazol-2-onehydrochloride (Compound 61b)

The titled compound was synthesized from Compound 61a obtained in Step61-1 by performing an operation similar to Step 11-8 of Example 11 usingan appropriate reagent.

LC/MS mass spectrometry: m/z 472 ([M+H]⁺).

LC/MS retention time: 0.79 min. (Analysis Condition: SMD-FA05-1).

Compound 62b used in the synthesis of Example Compound 62 wassynthesized by the following process.

<Step 62-1>

tert-Butyl(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-[1-(2-methoxyethyl)indazol-5-yl]-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (Compound 62a)

The titled compound was synthesized from Compound 11k obtained in Step11-7 and 5-bromo-1-(2-methoxyethyl)indazole (Compound 56a) by performingan operation similar to Step 1-11 of Example 1 using an appropriatereagent.

LC/MS mass spectrometry: m/z 616 ([M+H]⁺).

LC/MS retention time: 1.29 min. (Analysis Condition: SMD-FA05-1).

<Step 62-2>

1-[(4S)-2-(4-Fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-3-[1-(2-methoxyethyl)indazol-5-yl]imidazol-2-onehydrochloride (Compound 62b)

The titled compound was synthesized from Compound 62a obtained in Step62-1 by performing an operation similar to Step 11-8 of Example 11 usingan appropriate reagent.

LC/MS mass spectrometry: m/z 516 ([M+H]⁺).

LC/MS retention time: 0.76 min. (Analysis Condition: SMD-FA05-1).

Compound 63g used in the synthesis of Example Compound 63 wassynthesized by the following process.

<Step 63-1>

5-Bromo-7-fluoro-N-methyl-N-phenyl-1H-indole-2-carboxamide (Compound63b)

The titled compound was synthesized from5-bromo-7-fluoro-1H-indole-2-carboxylic acid (Compound 63a) byperforming an operation similar to Step 1-10 of Example 1 using anappropriate reagent.

<Step 63-2>

5-Bromo-1-(cyanomethyl)-7-fluoro-N-methyl-N-phenylindole-2-carboxamide(Compound 63c)

The titled compound was synthesized from Compound 63b obtained in Step63-1 by performing an operation similar to Step 9-1 of Example 9 usingan appropriate reagent.

LC/MS mass spectrometry: m/z 386 ([M+H]⁺).

LC/MS retention time: 3.17 min. (Analysis Condition: SMD-FA10-long).

<Step 63-3>

5-Bromo-1-[(1S,2S)-1-cyano-2-methylcyclopropyl]-7-fluoro-N-methyl-N-phenylindole-2-carboxamide(Compound 63d)

The titled compound was synthesized from Compound 63c obtained in Step63-2 by performing an operation similar to Step 1-6 of Example 1 usingan appropriate reagent.

LC/MS mass spectrometry: m/z 426 ([M+H]⁺).

LC/MS retention time: 1.36 min. (Analysis Condition: SMD-FA05-1).

¹H-NMR (300 MHz, CDCl₃) δ: 7.75 (1H, s), 7.43-7.30 (6H, m), 6.08 (1H,brs), 3.44 (3H, s), 2.11-1.69 (3H, m), 1.40-1.35 (3H, m).

<Step 63-4>

1-[(1S,2S)-1-Cyano-2-methylcyclopropyl]-7-fluoro-N-methyl-5-(oxan-4-yl)-N-phenylindole-2-carboxamide(Compound 63e)

The titled compound was synthesized from Compound 63d obtained in Step63-3 and (tetrahydro-2H-pyran-4-yl)zinc (II) iodide (Compound 8a) byperforming an operation similar to Step 8-1 of Example 8 using anappropriate reagent.

LC/MS mass spectrometry: m/z 432 ([M+H]⁺).

LC/MS retention time: 1.22 min. (Analysis Condition: SMD-FA05-1).

<Step 63-5>

7-Fluoro-N-methyl-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]-5-(oxan-4-yl)-N-phenylindole-2-carboxamide(Compound 63f)

The titled compound was synthesized from Compound 63e obtained in Step63-4 by performing an operation similar to Step 1-8 of Example 1 usingan appropriate reagent.

LC/MS mass spectrometry: m/z 491 ([M+H]⁺).

LC/MS retention time: 1.21 min. (Analysis Condition: SQD-FA05-01).

<Step 63-6>

7-Fluoro-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]-5-(oxan-4-yl)indole-2-carboxylicacid (Compound 63g)

The titled compound was synthesized from Compound 63f obtained in Step63-5 by performing an operation similar to Step 6-4 of Example 6 usingan appropriate reagent.

LC/MS mass spectrometry: m/z 402 ([M+H]⁺).

LC/MS retention time: 0.97 min. (Analysis Condition: SMD-FA05-1).

Compound 64b used in the synthesis of Example Compound 64 wassynthesized by the following process.

<Step 64-1>

tert-Butyl(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-[2-oxo-3-[1-[(3R)-oxolan-3-yl]indazol-5-yl]imidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate(Compound 64a)

The titled compound was synthesized from Compound 11k obtained in Step11-7 and Compound 8f obtained in Step 8-4 by performing an operationsimilar to Step 1-11 of Example 1 using an appropriate reagent.

LC/MS mass spectrometry: m/z 628 ([M+H]⁺).

LC/MS retention time: 1.32 min. (Analysis Condition: SMD-FA05-1).

<Step 64-2>

1-[(4S)-2-(4-Fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-3-[1-[(3R)-oxolan-3-yl]indazol-5-yl]imidazol-2-onehydrochloride (Compound 64b)

The titled compound was synthesized from Compound 64a obtained in Step64-1 by performing an operation similar to Step 11-8 of Example 11 usingan appropriate reagent.

LC/MS mass spectrometry: m/z 528 ([M+H]⁺).

LC/MS retention time: 0.78 min. (Analysis Condition: SMD-FA05-1).

Compound 65c used in the synthesis of Example Compound 65 wassynthesized by the following process.

<Step 65-1>

tert-Butyl(4S)-2-(4-chloro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate(Compound 65b)

The titled compound was synthesized from Compound 42e obtained in Step42-4 and 5-bromo-4-fluoro-1-methylindazole (Compound 65a) by performingan operation similar to Step 1-11 of Example 1 using an appropriatereagent.

LC/MS mass spectrometry: m/z 606 ([M+H]⁺).

LC/MS retention time: 1.38 min. (Analysis Condition: SMD-FA05-1).

<Step 65-2>

1-[(4S)-2-(4-Chloro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-3-(4-fluoro-1-methylindazol-5-yl)imidazol-2-onehydrochloride (Compound 65c)

The titled compound was synthesized from Compound 65b obtained in Step65-1 by performing an operation similar to Step 11-8 of Example 11 usingan appropriate reagent.

LC/MS mass spectrometry: m/z 506 ([M+H]⁺).

LC/MS retention time: 0.86 min. (Analysis Condition: SMD-FA05-1).

Compound 67b used in the synthesis of Example Compound 67 wassynthesized by the following process.

<Step 67-1>

tert-Butyl(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate(Compound 67a)

The titled compound was synthesized from Compound 11k obtained in Step11-7 and 5-bromo-4-fluoro-1-methylindazole (Compound 65a) by performingan operation similar to Step 1-11 of Example 1 using an appropriatereagent.

LC/MS mass spectrometry: m/z 590 ([M+H]⁺).

LC/MS retention time: 1.31 min. (Analysis Condition: SMD-FA05-1).

<Step 67-2>

1-[(4S)-2-(4-Fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-3-(4-fluoro-1-methylindazol-5-yl)imidazol-2-onehydrochloride (Compound 67b)

The titled compound was synthesized from Compound 67a obtained in Step67-1 by performing an operation similar to Step 11-8 of Example 11 usingan appropriate reagent.

LC/MS mass spectrometry: m/z 490 ([M+H]⁺).

LC/MS retention time: 0.80 min. (Analysis Condition: SQD-FA05-1).

Compound 68c used in the synthesis of Example Compound 68 wassynthesized by the following process.

<Step 68-1>

tert-Butyl(4S)-3-[3-(4-chloro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate(Compound 68b)

The titled compound was synthesized from Compound 11k obtained in Step11-7 and 5-bromo-4-chloro-1-methylindazole (Compound 68a) by performingan operation similar to Step 1-11 of Example 1 using an appropriatereagent.

LC/MS mass spectrometry: m/z 606 ([M+H]⁺).

LC/MS retention time: 1.34 min. (Analysis Condition: SMD-FA05-1).

<Step 68-2>

1-(4-Chloro-1-methylindazol-5-yl)-3-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]imidazol-2-onehydrochloride (Compound 68c)

The titled compound was synthesized from Compound 68b obtained in Step68-1 by performing an operation similar to Step 11-8 of Example 11 usingan appropriate reagent.

LC/MS mass spectrometry: m/z 506 ([M+H]⁺).

LC/MS retention time: 0.83 min. (Analysis Condition: SMD-FA05-1).

Compound 69b used in the synthesis of Example Compound 69 wassynthesized by the following process.

<Step 69-1>

tert-Butyl(4S)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-2-(4-fluoro-3-methylphenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate(Compound 69a)

The titled compound was synthesized from Compound 46d obtained in Step46-3 and 5-bromo-4-fluoro-1-methylindazole (Compound 65a) by performingan operation similar to Step 1-11 of Example 1 using an appropriatereagent.

LC/MS mass spectrometry: m/z 576 ([M+H]⁺).

LC/MS retention time: 1.25 min. (Analysis Condition: SMD-FA05-1).

<Step 69-2>

1-(4-Fluoro-1-methylindazol-5-yl)-3-[(4S)-2-(4-fluoro-3-methylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]imidazol-2-onehydrochloride (Compound 69b)

The titled compound was synthesized from Compound 69a obtained in Step69-1 by performing an operation similar to Step 11-8 of Example 11 usingan appropriate reagent.

LC/MS mass spectrometry: m/z 476 ([M+H]⁺).

LC/MS retention time: 0.77 min. (Analysis Condition: SMD-FA05-1).

Compound 70c used in the synthesis of Example Compound 70 wassynthesized by the following process.

<Step 70-1>

tert-Butyl(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(6-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate(Compound 70b)

The titled compound was synthesized from Compound 11k obtained in Step11-7 and 5-bromo-6-fluoro-1-methylindazole (Compound 70a) by performingan operation similar to Step 1-11 of Example 1 using an appropriatereagent.

LC/MS mass spectrometry: m/z 590 ([M+H]⁺).

LC/MS retention time: 1.28 min. (Analysis Condition: SMD-FA05-1).

<Step 70-2>

1-[(4S)-2-(4-Fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-3-(6-fluoro-1-methylindazol-5-yl)imidazol-2-onehydrochloride (Compound 70c)

The titled compound was synthesized from Compound 70b obtained in Step70-1 by performing an operation similar to Step 11-8 of Example 11 usingan appropriate reagent.

LC/MS mass spectrometry: m/z 490 ([M+H]⁺).

LC/MS retention time: 0.81 min. (Analysis Condition: SMD-FA05-1).

Compound 71b used in the synthesis of Example Compound 71 wassynthesized by the following process.

<Step 71-1>

5-Bromo-6-fluoro-1-(2-methoxyethyl)indazole (Compound 71b)

The titled compound was synthesized from 5-bromo-6-fluoro-1H-indazole(Compound 71a) by performing an operation similar to Step 8-4 of Example8 using an appropriate reagent.

LC/MS mass spectrometry: m/z 273 ([M+H]⁺).

LC/MS retention time: 1.06 min. (Analysis Condition: SMD-FA05-1).

<Step 71-2>

tert-Butyl(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-[6-fluoro-1-(2-methoxyethyl)indazol-5-yl]-2-oxoimidazol-1l-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate(Compound 71c)

The titled compound was synthesized from Compound 11k obtained in Step11-7 and Compound 71b obtained in Step 71-1 by performing an operationsimilar to Step 1-11 of Example 1 using an appropriate reagent.

LC/MS mass spectrometry: m/z 634 ([M+H]⁺).

LC/MS retention time: 1.30 min. (Analysis Condition: SMD-FA05-1).

<Step 71-3>

1-[(4S)-2-(4-Fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-3-[6-fluoro-1-(2-methoxyethyl)indazol-5-yl]imidazol-2-onehydrochloride (Compound 71d)

The titled compound was synthesized from Compound 71c obtained in Step71-2 by performing an operation similar to Step 11-8 of Example 11 usingan appropriate reagent.

LC/MS mass spectrometry: m/z 534 ([M+H]⁺).

LC/MS retention time: 0.83 min. (Analysis Condition: SMD-FA05-1).

<Example 73> Synthesis of3-[(1S,2S)-1-[5-(2-ethyl-3-methylpyridin-4-yl)-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-[3-(1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one(Compound 73)

<Step 73-1>

To a DMF (1.5 mL) solution of a racemic form (Compound 73a, 29.6 mg,0.058 mmol) synthesized by a method similar to the compound obtained inStep 61-2 and Compound 10 (26.8 mg, 0.064 mmol) obtained in Step 1-9were added HATU (26.6 mg, 0.070 mmol) and N,N-diisopropylethylamine(18.1 mg, 0.14 mmol), and the mixture was stirred at room temperaturefor an hour. The reaction solution was diluted by ethyl acetate, andwashed with distilled water. The organic layer was concentrated underreduced pressure to obtain a residue which is a mixture ofstereoisomers. The stereoisomers were separated by reversed-phase HPLCto obtain Entity A (14.5 mg, yield 29%) and Entity B (15.5 mg, yield31%), which is a white, solid, titled Compound 73.

Separation Condition

-   -   Column: YMC Actus ODS-A, 20×100 mm, 5 m    -   Solvent: 0.1% formic acid aqueous solution/0.1% formic acid        acetonitrile solution=40/60 (homogenous system)    -   Flow rate: 20 mL/min., room temperature

Entity A

LC/MS mass spectrometry: m/z 872 ([M+H]⁺).

LC/MS retention time: 0.99 min. (Analysis Condition: SMD-FA05-3).

Entity B (Compound 73)

LC/MS mass spectrometry: m/z 872 ([M+H]⁺).

LC/MS retention time: 1.01 min. (Analysis Condition: SMD-FA05-3).

<Example 74> Synthesis of3-[(1S,2S)-1-[6-Fluoro-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-[3-(1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(2-methoxy-3-methylpyridin-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one(Compound 74)

[Chemical Formula 67]

<Step 74-1>

5-Bromo-6-fluoro-N-methyl-N-phenyl-1H-indole-2-carboxamide (Compound74b)

The titled compound was synthesized from5-bromo-6-fluoro-1H-indole-2-carboxylic acid (Compound 74a) byperforming an operation similar to Step 1-10 of Example 1 using anappropriate reagent.

LC/MS mass spectrometry: m/z 347 ([M+H]⁺).

LC/MS retention time: 1.06 min. (Analysis Condition: SMD-TFA05-4).

<Step 74-2>

5-Bromo-1-(cyanomethyl)-6-fluoro-N-methyl-N-phenylindole-2-carboxamide(Compound 74c)

The titled compound was synthesized from Compound 74b obtained in Step74-1 by performing an operation similar to Step 9-1 of Example 9 usingan appropriate reagent.

LC/MS mass spectrometry: m/z 386 ([M+H]⁺).

LC/MS retention time: 1.06 min. (Analysis Condition: SMD-TFA50-4).

<Step 74-3>

5-Bromo-1-[(1S,2S)-1-cyano-2-methylcyclopropyl]-6-fluoro-N-methyl-N-phenylindole-2-carboxamide(Compound 74d)

The titled compound was synthesized from Compound 74c obtained in Step74-2 and (4R)-4-methyl-1,3,2-dioxathiolane 2,2-dioxide (Compound 1k) byperforming an operation similar to Step 1-6 of Example 1 using anappropriate reagent.

LC/MS mass spectrometry: m/z 426 ([M+H]⁺).

LC/MS retention time: 1.04 min. (Analysis Condition: SMD-FA10-5).

<Step 74-4>

5-Bromo-6-fluoro-N-methyl-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]-N-phenylindole-2-carboxamide(Compound 74e)

The titled compound was synthesized from Compound 74d obtained in Step74-3 by performing an operation similar to Step 1-8 of Example 1 usingan appropriate reagent.

LC/MS mass spectrometry: m/z 485 ([M+H]⁺).

LC/MS retention time: 1.33 min. (Analysis Condition: SMD-FA05-1).

<Step 74-5>

5-Bromo-6-fluoro-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carboxylicacid (Compound 74f)

The titled compound was synthesized from Compound 74e obtained in Step74-4 by performing an operation similar to Step 6-4 of Example 6 usingan appropriate reagent.

LC/MS mass spectrometry: m/z 396 ([M+H]⁺).

LC/MS retention time: 0.80 min. (Analysis Condition: SQD-FA05-1).

<Step 74-6>

3-[(1S,2S)-1-[5-Bromo-6-fluoro-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-[3-(1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one(Compound 74g)

The titled compound was synthesized from Compound 74f obtained in Step74-5 and Compound 61b obtained in Step 61-2 by performing an operationsimilar to Step 1-10 of Example 1 using an appropriate reagent.

LC/MS mass spectrometry: m/z 849 ([M+H]⁺).

LC/MS retention time: 1.42 min. (Analysis Condition: SMD-FA05-1).

<Step 74-7>

3-[(1S,2S)-1-[6-Fluoro-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-[3-(1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(2-methoxy-3-methylpyridin-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one(Compound 74)

The titled compound was synthesized by performing an operation similarto Step 6-5 of Example 6 using Compound 74g obtained in Step 74-6 and4-iodo-2-methoxy3-methylpyridine (Compound 6g), and an appropriatereagent.

LC/MS mass spectrometry: m/z 892 ([M+H]⁺).

LC/MS retention time: 1.48 min. (Analysis Condition: SMD-TFA05-1).

Examples 75-77

An operation similar to Step 8-1 of Example 8 was performed using anindole bromide compound and an iodo (oxan-4-yl) zinc derivative, and anappropriate reagent to obtain Example Compounds 75 to 77 shown in Table2-6 by the following reaction.

TABLE 2-6 The Obtained Example Compounds 75 to 77 LC/MS LC/MS massretention spectro- Example Analysis time metry No. Structure CompoundCondition (min.) (m/z) 75

3-[(1S,2S)-1-[2-[2-(4- fluoro-3,5- dimethylphenyl)-3-[3-(1-methylindazol-5-yl)-2- oxoimidazol-1-yl]-6,7- dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5- (6-oxaspiro[4.5]decan-9- yl)indol-1-yl]-2-methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-one SMD- TFA05-2 1.57 878([M+H]⁺) 76

3-[(1S,2S)-1-[5-(2,2- dimethyloxan-4-yl)-2-[2- (4-fluoro-3,5-dimethylphenyl)-3-[3-[1- (2-methoxyethyl)indazol-5-yl]-2-oxoimidazol-1-yl]- 6,7-dihydro-4H- pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2- methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-oneSMD- TFA05-2 1.44 895 ([M+H]⁺) 77

3-[(1S,2S)-1-[5-[(2S,4S)- (2-ethyloxan-4-yl)-2-[2-(4- fluoro-3,5-dimethylphenyl)-3-[3-(1- methylindazol-5-yl)-2- oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3- c]pyridine-5- carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-one SMD- TFA05-2 1.51 851([M+H]⁺)

Compound 75b used in the synthesis of Example Compound 75 wassynthesized by the following process.

<Step 75-1>

Iodo(6-oxaspiro[4.5]decan-9-yl) zinc (Compound 75b)

The titled compound was synthesized from 9-iodo-6-oxaspiro[4.5]decane(Compound 75a) by performing an operation similar to Step 41-1 ofExample 41 using an appropriate reagent.

The compound was directly put to use in the next step.

Compound 76a used in the synthesis of Example Compound 76 wassynthesized by the following process.

<Step 76-1>

3-[(1S,2S)-1-[5-Bromo-2-[2-(4-fluoro-3,5-dimethylphenyl)-3-[3-[1-(2-methoxyethyl)indazol-5-yl]-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one(Compound 76a)

The titled compound was synthesized from Compound 56b obtained in Step56-1 and Compound 6f obtained in Step 6-4 by performing an operationsimilar to Step 1-10 of Example 1 using an appropriate reagent.

LC/MS mass spectrometry: m/z 861 ([M+H]⁺).

LC/MS retention time: 1.45 min. (Analysis Condition: SMD-FA05-2).

Example 77

<Step 77-1>

2-Ethyl-4-iodooxane (Compound 77b)

To an acetic acid (2.48 mL) solution of but-3-en-1-ol (0.588 mL, 6.93mmol) was sequentially added propionaldehyde (0.650 mL, 9.01 mmol) andlithium iodide (2.78 g, 20.8 mmol), and the mixture was stirred at 60°C. for 1 h. Water was added to the reaction mixture, and extraction wasperformed using dichloromethane. The organic layer was washed with 10%sodium thiosulfate aqueous solution and saturated sodium acid carbonateaqueous solution, then dried with magnesium sulfate. After filtration,the filtrate was concentrated under reduced pressure (lower limit being150 hpa), and the residue was purified by silica gel chromatography(ethyl acetate/hexane=0:1 to 1:9) to obtain the titled Compound 77b as apale yellow oil-like diastereomer mixture (1.12 g, yield 67%,syn:anti=1.00:0.45).

¹H-NMR (400 MHz, CDCl₃):

syn δ: 4.31-4.23 (1H, m), 3.90-3.82 (1H, m), 3.44-3.37 (1H, m),3.21-3.15 (1H, m), 2.37-1.38 (6H, m), 0.92 (3H, t, J=7.4 Hz).

anti δ: 4.87-4.84 (1H, m), 3.90-3.82 (2H, m), 3.70-3.64 (1H, m),2.37-1.38 (6H, m), 0.94 (3H, t, J=7.6 Hz).

<Step 77-2>

(2-Ethyloxan-4-yl)-iodozinc (Compound 77c)

To a DMA (0.25 mL) solution of zinc (102 mg, 1.56 mmol) was slowly addeddropwise a mixture of chloro(trimethyl)silane (0.017 mL, 0.137 mmol) and1,2-dibromoethane (0.012 mL, 0.137 mmol) under a nitrogen atmospherewhile maintaining a temperature of 65° C. or lower, and the mixture wasstirred at room temperature for 15 min. Then, the DMA (0.625 mL)solution of Compound 77b (300 mg, 1.25 mmol) obtained in Step 77-1 wasadded dropwise slowly into the mixture while maintaining a temperatureof 65° C. or lower, and the mixture was stirred under a nitrogenatmosphere at room temperature for 30 min. to obtain a DMA solution(0.86M) of a diastereomer mixture of the titled Compound 77c.

<Step 77-3>

3-[(1S,2S)-1-[5-(2-Ethyloxan-4-yl)-2-[2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one(Compound 77)

To a DMA (0.163 mL) solution of Compound 51d (40.0 mg, 0.049 mmol)obtained in Step 51-4 were added palladium(II) acetate (2.20 mg, 0.00978mmol), and2-(2-dicyclohexylphosphanylphenyl)-1-N,1-N,3-N,3-N-tetramethylbenzene-1,3-diamine(8.54 mg, 0.020 mmol), and the mixture was deaerated under reducedpressure, then nitrogen was introduced in the vessel and the mixture wasstirred at room temperature for 5 min. Then, a DMA (0.86 M, 0.398 mL,0.342 mmol) solution of Compound 77c obtained in Step 77-2 was added andthe mixture was stirred at room temperature for 1.5 h. Formic acid wasadded to the reaction mixture, and the reaction mixture was purified byreversed-phase silica gel chromatography (acetonitrile/water, 0.1%formic acid) to obtain the syn-type diastereomer mixture. The syn-typediastereomer mixture was separated into stereoisomers by thereversed-phase HPLC to obtain a white, amorphous Entity A (17.4 mg,yield 41%) and a white, amorphous Entity B (14.9 mg, yield 37%), whichis the titled Compound 77.

Separation Condition

-   -   Column: CHIRALCEL OD-RH 5 m, 4.6 mmx 150 mm (Daicel)    -   Solvent: 0.1% formic acid aqueous solution/0.1% formic acid        acetonitrile solution=20/80 (homogenous system)    -   Flow rate: 1.0 mL/min., room temperature

Entity A

LC/MS mass spectrometry: m/z 851 ([M+H]⁺).

HPLC retention time: 4.99 min. (Separation condition).

LC/MS retention time: 1.46 min. (Analysis Condition: SMD-FA05-1).

Entity B (Compound 77)

LC/MS mass spectrometry: m/z 851 ([M+H]⁺).

HPLC retention time: 6.64 min. (Separation condition).

LC/MS retention time: 1.46 min. (Analysis Condition: SMD-FA05-1).

<Example 78> Synthesis of3-[(1S,2S)-2-Ethyl-1-[2-[2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4-yl)indol-1-yl]cyclopropyl]-4H-1.2.4-oxadiazol-5-one(Compound 78)

<Step 78-1>

2-[5-Bromo-2-[2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]acetonitrile(Compound 78a)

The titled compound was synthesized from Compound 51c obtained in Step51-3 and 5-bromo-1-(cyanomethyl)indole-2-carboxylic acid (Compound 6a)by performing an operation similar to Step 1-10 of Example 1 using anappropriate reagent.

LC/MS mass spectrometry: m/z 718 ([M+H]⁺).

LC/MS retention time: 1.30 min. (Analysis Condition: SMD-FA05-1).

<Step 78-2>

2-[2-[2-(4-Fluoro-3,5-dimethylphenyl)-3-[3-(1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4-yl)indol-1-yl]acetonitrile(Compound 78b)

The titled compound was synthesized from Compound 78a obtained in Step78-1 and (tetrahydro-2H-pyran-4-yl)zinc (II) iodide (Compound 8a) byperforming an operation similar to Step 8-1 of Example 8 using anappropriate reagent.

LC/MS mass spectrometry: m/z 724 ([M+H]⁺).

LC/MS retention time: 1.21 min. (Analysis Condition: SMD-FA05-1).

<Step 78-3>

(1S,2S)-2-Ethyl-1-[2-[2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4-yl)indol-1-yl]cyclopropane-1-carbonitrile(Compound 78d)

The titled compound was synthesized from Compound 78b obtained in Step78-2 by performing an operation similar to Step 1-6 of Example 1 usingan appropriate reagent.

LC/MS mass spectrometry: m/z 778 ([M+H]⁺).

LC/MS retention time: 1.27 min. (Analysis Condition: SMD-FA05-RP).

<Step 78-4>

3-[(1S,2S)-2-Ethyl-1-[2-[2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4-yl)indol-1-yl]cyclopropyl]-4H-1,2,4-oxadiazol-5-one(Compound 78)

The titled compound was synthesized from Compound 78d obtained in Step78-2 by performing an operation similar to Step 1-8 of Example 1 usingan appropriate reagent.

LC/MS mass spectrometry: m/z 837 ([M+H]⁺).

LC/MS retention time: 1.39 min. (Analysis Condition: SMD-TFA05-2).

<Example 79> Synthesis of3-[(1S,2S)-1-[2-[2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4-yl)indol-1-yl]-2-(hydroxymethyl)cyclopropyl]-4H-1,2,4-oxadiazol-5-one(Compound 79)

<Step 79-1>

5-Bromo-1-[(1S,2S)-1-cyano-2-(phenylmethoxymethyl)cyclopropyl]-N-methyl-N-phenylindole-2-carboxamide(Compound 79b)

The titled compound was synthesized from Compound 6c obtained in Step6-1 and (4R)-4-(phenylmethoxymethyl)-1,3,2-dioxathiolane 2,2-dioxide(Compound 79a) by performing an operation similar to Step 1-6 of Example1 using an appropriate reagent.

LC/MS mass spectrometry: m/z 514 ([M+H]⁺).

LC/MS retention time: 1.48 min. (Analysis Condition: SMD-FA05-1).

<Step 79-2>

1-[(1S,2S)-1-Cyano-2-(phenylmethoxymethyl)cyclopropyl]-N-methyl-5-(oxan-4-yl)-N-phenylindole-2-carboxamide(Compound 79c)

The titled compound was synthesized from Compound 79b obtained in Step79-1 and (tetrahydro-2H-pyran-4-yl)zinc (II) iodide (Compound 8a) byperforming an operation similar to Step 8-1 of Example 8 using anappropriate reagent.

LC/MS mass spectrometry: m/z 520 ([M+H]⁺).

LC/MS retention time: 1.37 min. (Analysis Condition: SMD-FA05-1).

<Step 79-3>

N-Methyl-5-(oxan-4-yl)-1-[(1S,2S)-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)-2-(phenylmethoxymethyl)cyclopropyl]-N-phenylindole-2-carboxamide(Compound 79d)

The titled compound was synthesized from Compound 79c obtained in Step79-2 by performing an operation similar to Step 1-8 of Example 1 usingan appropriate reagent.

LC/MS mass spectrometry: m/z 579 ([M+H]⁺).

LC/MS retention time: 1.37 min. (Analysis Condition: SMD-FA05-1).

<Step 79-4>

5-(Oxan-4-yl)-1-[(1S,2S)-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)-2-(phenylmethoxymethyl)cyclopropyl]indole-2-carboxylicacid (Compound 79e)

The titled compound was synthesized from Compound 79d obtained in Step79-3 by performing an operation similar to Step 6-4 of Example 6 usingan appropriate reagent.

LC/MS mass spectrometry: m/z 490 ([M+H]⁺).

LC/MS retention time: 1.12 min. (Analysis Condition: SMD-FA05-1).

<Step 79-5>

3-[(1S,2S)-1-[2-[2-(4-Fluoro-3,5-dimethylphenyl)-3-[3-(1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4-yl)indol-1-yl]-2-(phenylmethoxymethyl)cyclopropyl]-4H-1,2,4-oxadiazol-5-one(Compound 79f)

The titled compound was synthesized from Compound 79e obtained in Step79-4 and Compound 51c obtained in Step 51-3 by performing an operationsimilar to Step 1-10 of Example 1 using an appropriate reagent.

LC/MS mass spectrometry: m/z 929 ([M+H]⁺).

LC/MS retention time: 1.41 min. (Analysis Condition: SMD-FA05-1).

<Step 79-6>

3-[(1S,2S)-1-[2-[2-(4-Fluoro-3,5-dimethylphenyl)-3-[3-(1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4-yl)indol-1-yl]-2-(hydroxymethyl)cyclopropyl]-4H-1,2,4-oxadiazol-5-one(Compound 79)

The dichloromethane (0.762 mL) solution of Compound 79f (35.4 mg, 0.0381mmol) obtained in Step 79-5 was cooled to 0° C., and a hexane solution(0.191 mL, 0.191 mmol) of 1M boron trichloride was slowly added. Thereaction solution was warmed to room temperature and stirred for 105min., and then a saturated sodium acid carbonate solution was added tothe reaction solution and the water layer was subjected to extractionusing dichloromethane. The organic layer was washed with brine and driedwith sodium sulfate. After filtration, the filtrate was concentratedunder reduced pressure and the residue was purified by reversed-phasecolumn chromatography (acetonitrile/water, 0.1% formic acid) to obtainthe titled compound (18.5 mg, yield 50%).

LC/MS mass spectrometry: m/z 839 ([M+H]⁺).

LC/MS retention time: 1.20 min. (Analysis Condition: SMD-TFA05-1).

<Example 80> Synthesis of3-[(1S,2S)-1-[2-[(4S,6R)-2-(4-fluoro-3,5-dimethylphenyl)-4,6-dimethyl-3-[3-(1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one(Compound 80)

<Step 80-1>

Ethyl (E)-3-[[(2S)-1-Cyanopropan-2-yl]amino]but-2-enoate (Compound 80c)

To an acetonitrile (50 mL) solution of (3S)-3-aminobutanenitrile(Compound 80b, 7.0 g, 83.2 mmol) and iodine (2.12 g, 8.35 mmol) wasadded ethyl 3-oxobutanoate (Compound 80a, 13 g, 99.9 mmol), and themixture was stirred at room temperature for 4 h. The reaction solutionwas concentrated under reduced pressure and the solvent was removed byevaporation, and then the residue was purified by silica gel columnchromatography (petroleum ether/ethyl acetate=1:0 to 3:2) to obtain thetitled Compound 80c (9.5 g, yield 58%) as a yellow oil-like material.

LC/MS mass spectrometry: m/z 197 ([M+H]⁺).

LC/MS retention time: 0.86 min. (Analysis Condition: SMD-FA10-1).

<Step 80-2>

Ethyl 3-[[(2S)-1-Cyanopropan-2-yl]amino]butanoate (Compound 80d)

To a dichloromethane (200 mL) solution of Compound 80c (10 g, 51.0 mmol)obtained in Step 80-1 and sodium triacetoxyborohydride (43.3 g, 204mmol) was added acetic acid (3 mL), and the mixture was stirred at roomtemperature for 16 h. Water and acetic acid were added to the reactionsolution, and the pH was adjusted to 5, and then the water layer wassubjected to extraction using ethyl acetate. The organic layer waswashed with brine and dried using sodium sulfate. After filtration, thefiltrate was concentrated under reduced pressure, and the residue waspurified by silica gel column chromatography (petroleum ether/ethylacetate=1:0 to 1:4) to obtain the titled Compound 80d (5.5 g, yield 54%)as a yellow oil-like material.

LC/MS retention time: 0.83 min. (Analysis Condition: SMD-FA10-4).

<Step 80-3>

(6S)-1-Formyl-4-hydroxy-2,6-dimethyl-3,6-dihydro-2H-pyridine-5-carbonitrile(Compound 80e)

A toluene (5 mL) solution of Compound 80d (1.0 g, 5.04 mmol) obtained inStep 80-2 was added dropwise slowly at 80° C. to a toluene (10 mL)solution of potassium tert-butoxide (680 mg, 6.06 mmol). After thesolution was stirred at 80° C. for 1 h., the solution was cooled to roomtemperature to obtain a toluene solution of(6S)-4-hydroxy-2,6-dimethyl-1,2,3,6-tetrahydropyridine-5-carbonitrile.

A toluene (5 mL) solution of acetic anhydride (12.1 g, 118 mmol) wasadded dropwise slowly into formic acid (7.26 g) at 0° C. and stirred at0° C. for 30 min., and then the toluene solution of(6S)-4-hydroxy-2,6-dimethyl-1,2,3,6-tetrahydropyridine-5-carbonitrilethat had been prepared was added dropwise slowly. After the reactionsolution was stirred at 110° C. for 16 h., it was cooled to roomtemperature and concentrated under reduced pressure to remove thesolvent by evaporation, and a mixture (1.3 g) containing the titledCompound 80e was obtained as an oil-like material.

<Step 80-4>

(4S)-3-Amino-2-(4-fluoro-3,5-dimethylphenyl)-4,6-dimethyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbaldehyde(Compound 80f)

The ethanol (30 mL) solution of Compound 80e (1.30 g, 7.21 mmol)obtained in Step 80-3 and (4-fluoro-3,5-dimethylphenyl)hydrazinehydrochloride (Compound 2c, 690 mg, 3.62 mmol) was heated to 75° C. andwas stirred for 16 h. The reaction solution was cooled to roomtemperature and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography(dichloromethane/methanol=1:0 to 9:1), and the titled Compound 80f (2steps from Step 80-3, 800 mg, yield 35%) was obtained as a yellow solid.

LC/MS mass spectrometry: m/z 317 ([M+H]⁺).

LC/MS retention time: 0.79 min. (Analysis Condition: SMD-FA10-3).

<Step 80-5>

1-(2,2-Dimethoxyethyl)-3-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-5-formyl-4,6-dimethyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl]urea(Compound 80g)

2,2-Dimethoxyethane-1-amine (1.14 g, 10.8 mmol) was added at 0° C. to aDMA (50 mL) solution of N,N′-carbodiimidazole (1.63 g, 10.1 mmol), andthe mixture was stirred for 30 min. To the solution was addedsequentially potassium tert-butoxide (5.62 g, 50.1 mmol) and Compound80f (2.64 g, 8.34 mmol) obtained in Step 80-4. After the mixture wasstirred at room temperature for 6 h., water was added, and the waterlayer was subjected to extraction using ethyl acetate. After the organiclayer was washed with brine, it was dried with sodium sulfate. Afterfiltration, the filtrate was concentrated under reduced pressure toobtain the titled Compound 80g (2.80 g, yield 75%) as a brown oil-likematerial.

LC/MS mass spectrometry: m/z 448 ([M+H]⁺).

LC/MS retention time: 0.84 min. (Analysis Condition: SMD-FA10-2).

<Step 80-6>

(4S,6R)-2-(4-Fluoro-3,5-dimethylphenyl)-4,6-dimethyl-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbaldehyde(Compound 80h)

A DMF (30 mL) solution of Compound 80g (2.50 g, 5.59 mmol) obtained inStep 80-5 and 4-methylbenzenesulfonic acid (1.06 g, 6.16 mmol) washeated to 80° C. and stirred for 2 h. After the solution was cooled toroom temperature, water was added and the water layer was subjected toextraction using ethyl acetate. The organic layer was washed with brine,and dried with sodium sulfate. After filtration, the filtrate wasconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (petroleum ether/ethyl acetate=1:0to 3:1), to obtain the diastereomer mixture (480 mg) containing thetitled compound (Compound 80h) as a white solid.

LC/MS mass spectrometry: m/z 384 ([M+H]⁺).

LC/MS retention time: 1.64 min. (Analysis Condition: SMD-TFA05-6).

The diastereomer mixture (480 mg, 5.59 mmol) containing the titledcompound (Compound 80h:(4S,6R)-2-(4-fluoro-3,5-dimethylphenyl)-4,6-dimethyl-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbaldehyde)was separated to stereoisomers by SFC to obtain Entity A (155 mg, yield7.0%) which is the titled Compound 80h and Entity B (270 mg, yield 12%).

SFC Separation Condition

Column: CHIRALPAK AD-H, 50×500 mm, 3 μm (Daicel)

Solvent: supercritical carbon dioxide/ethanol=70:30 (homogenous system)

Flow rate: 150 mL/min., 35° C.

Detected wavelength: 254 nm

Entity A (Compound 80h)

SFC retention time: 4.07 min.

LC/MS mass spectrometry: m/z 384 ([M+H]⁺).

LC/MS retention time: 2.15 min. (Analysis Condition: SMD-FA1060-1).

¹H-NMR (300 MHz, DMSO-D₆) δ:10.35 (1H, s), 8.24 (1H, s), 7.11 (2H, d,J=6.3 Hz), 6.60-6.58 (2H, m), 5.21-5.14 (1H, m), 4.46-4.21 (1H, m),2.96-2.89 (1H, m), 2.74-2.68 (1H, m), 2.20 (6H, s), 1.27-1.13 (6H, m).

Note that the Compound 80h was determined to be the R-isomer from theresult obtained by 2D-NOESY that the steric configuration thereof is acis configuration.

Entity B

SFC retention time: 5.60 min.

LC/MS mass spectrometry: m/z 384 ([M+H]⁺).

LC/MS retention time: 2.16 min. (Analysis Condition: SMD-FA1060-1).

¹H-NMR (300 MHz, DMSO-D₆) δ:10.35 (1H, s), 8.31 (1H, s), 7.08 (2H, d,J=6.3 Hz), 6.61-6.54 (2H, m), 5.39 (1H, q, J=6.9 Hz), 3.89-3.84 (1H, m),2.90 (1H, dd, J=3.3, 15.6 Hz), 2.59-2.51 (1H, m), 2.20 (6H, d, J=2.1Hz), 1.55 (3H, d, J=6.6 Hz), 1.18 (3H, d, J=6.6 Hz).

<Step 80-7>

3-[(4S,6R)-2-(4-Fluoro-3,5-dimethylphenyl)-4,6-dimethyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-1H-imidazol-2-one(Compound 80i)

5M Sodium hydroxide solution (0.261 mL) was added to an ethanol (1.0 mL)solution of Compound 80h (100 mg, 0.261 mmol) obtained in Step 80-6, andthe mixture was stirred at 80° C. for 10 h. After the mixture was cooledto room temperature and stirred for 60 h., saturated ammonium chlorideaqueous solution was added and the mixture was subjected to extractionusing ethyl acetate to synthesize the titled Compound 801 (79%, 73 mg)as a white solid.

LC/MS mass spectrometry: m/z 356 ([M+H]⁺).

LC/MS retention time: 0.44 min. (Analysis Condition: SQD-FA05-2).

<Step 80-8>

1-[(4S,6R)-2-(4-Fluoro-3,5-dimethylphenyl)-4,6-dimethyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-3-(1-methylindazol-5-yl)imidazol-2-one(Compound 80j)

Copper iodide (I) (4.02 mg, 0.021 mmol) was added at a room temperatureto a N-methylpiperazine (0.188 mL) suspension of Compound 801 (15 mg,0.042 mmol) obtained in Step 80-7, 5-bromo-1-methylindazole (Compound1q, 10.7 mg, 0.051 mmol),(1S,2S)-1-N,2-N-dimethylcyclohexane-1,2-diamine (6.00 mg, 0.042 mmol),and potassium carbonate (17.5 mg, 0.127 mmol), and the mixture wasstirred under a nitrogen atmosphere at 130° C. for 90 min. The reactionmixture was purified by reversed-phase silica gel chromatography(acetonitrile/water, 0.1% formic acid) and concentrated under a reducedpressure. A saturated sodium acid carbonate aqueous solution was addedto the residue, and extraction was performed using ethyl acetate, andthen the organic layer was concentrated under reduced pressure to obtainthe titled Compound 80j (17.4 mg, yield 85%).

LC/MS mass spectrometry: m/z 486 ([M+H]⁺).

LC/MS retention time: 0.51 min. (Analysis Condition: SQD-FA05-2).

<Step 80-9>

2-Trimethylsilylethoxymethyl5-(oxan-4-yl)-1-[(1S,2S)-2-[5-oxo-4-(2-trimethylsilylethoxymethyl)-1,2,4-oxadiazol-3-yl]-2-methylcyclopropyl]indole-2-carboxylate(Compound 80k)

To a DMF (2.6 mL) solution of Compound 8b (100 mg, 0.261 mmol) obtainedin Step 8-1 was added 55 wt % sodium hydride (34.1 mg, 0.782 mmol) and2-(trimethylsilyl)ethoxymethylchloride (0.116 mL, 0.652 mmol), and themixture was stirred under room temperature for 1 h. A saturated ammoniumchloride solution was added, and extraction was performed using ethylacetate. Then, the residue obtained after concentration was purified bynormal phase column chromatography (ethyl acetate/hexane) to obtain thetitled Compound 80k (147 mg, yield 88%) as a yellow gum-like material.

LC/MS retention time: 1.21 min. (Analysis Condition: SQD-FA05-2).

<Step 80-10>

5-(Oxan-4-yl)-1-[(1S,2S)-1-[5-oxo-4-(2-trimethylsilylethoxymethyl)-1,2,4-oxadiazol-3-yl]-2-methylcyclopropyl]indole-2-carboxylicacid (801)

To a dichloromethane (2.3 mL) solution of Compound 80k (147 mg, 0.228mmol) obtained in Step 80-9 was added a magnesium bromide/diethyl ethercomplex (295 mg, 1.14 mmol), and the mixture was stirred at 0° C. for6.5 h. The mixture was warmed to room temperature and stirred for 30min., and then a saturated ammonium chloride aqueous solution was added.Then, extraction was performed using ethyl acetate, and the resultingproduct was concentrated, and then the residue was diluted with DMSO andwater and purified by reversed-phase chromatography (acetonitrile/water,0.1% formic acid) to synthesize the titled Compound 801 (60 mg, yield51%).

LC/MS mass spectrometry: m/z 512 ([M−H]⁻).

LC/MS retention time: 1.03 min. (Analysis Condition: SQD-FA05-2).

<Step 80-11>

5-(Oxan-4-yl)-1-[(1S,2S)-2-[5-oxo-4-(2-trimethylsilylethoxymethyl)-1,2,4-oxadiazol-3-yl]-2-methylcyclopropyl]indole-2-carbonylchloride(Compound 80m)

To an acetonitrile (0.36 mL) solution of Compound 801 (18 mg, 0.036mmol) obtained in Step 80-10 was added1-chloro-N,N,2-trimethylprop-1-en-1-amine (0.0057 mg, 0.043 mmol), andthe mixture was stirred at room temperauter for 2 h., and then it wasconcentrated to obtain a crude product of the titled Compound 80m. Thiscompound was directly put to use in the next step.

<Step 80-12>

3-[(1S,2S)-2-[2-[(4S,6R)-2-(4-Fluoro-3,5-dimethylphenyl)-4,6-dimethyl-3-[3-(1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4-yl)indol-1-yl]-2-methylcyclopropyl]-4-(2-trimethylsilylethoxymethyl)-1,2,4-oxadiazol-5-one(Compound 80n)

Compound 80m obtained in Step 80-11 was dissolved in THF (0.717 mL), andCompound 80j (19.1 mg, 0.036 mmol) obtained in Step 80-8 andN,N-diisopropylethylamine (0.0188 mL, 0.108 mmol) were added to thesolution, then the mixture was stirred at room temperature for 22 h.,and then methanol and formic acid were added. The mixture wasconcentrated, and the residue was diluted with DMSO and water andpurified by reversed-phase column chromatography (acetonitrile/water,0.1% formic acid) to synthesize the titled Compound 80n (32 mg, yield91%).

LC/MS mass spectrometry: m/z 982 ([M+H]⁺).

LC/MS retention time: 1.12 min. (Analysis Condition: SQD-FA50-1).

<Step 80-13>

3-[(1S,2S)-1-[2-[(4S,6R)-2-(4-Fluoro-3,5-dimethylphenyl)-4,6-dimethyl-3-[3-(1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one(Compound 80)

To a THF (0.326 mL) solution of Compound 80n (32 mg, 0.033 mmol)obtained in Step 80-12 was added acetic acid (0.0019 mL, 0.033 mmol) anda THF solution (0.065 mL, 0.065 mmol) of 1M tetrabutylammonium fluoride,and the mixture was stirred at 80° C. for 66 h. Acetic acid (0.0019 mL,0.033 mmol) and a THF solution (0.065 mL, 0.065 mmol) of 1Mtetrabutylammonium fluoride were added, and the mixture was stirred for23.5 h. Further, a THF solution (0.065 mL, 0.065 mmol) of 1Mtetrabutylammonium fluoride was added, then the mixture was stirred for7 h., and then formic acid was added. After concentration, the mixturewas diluted with DMSO and water and purified by reversed-phase columnchromatography (acetonitrile/water, 0.100 formic acid) to synthesize thetitled Compound 80C (18 mg, yield 65%).

LC/MS mass spectrometry: m/z 851 ([M+H]⁺).

LC/MS retention time: 1.42 min. (Analysis Condition: SMD-TFA05-1).

Example Compounds 101 to 159 shown in Table 2-7 below was obtainedsimilarly to Examples 1 to 80.

TABLE 2-7 The Obtained Example Compounds 101 to 159 LC/MS LC/MS massretention spectro- Example Analysis time metry No. Structure CompoundCondition (min.) (m/z) 101

3-[(1S,2S)-1-[5-(2-ethyl- 3-methylpyridin-4-yl)-2- [2-(4-fluoro-3,5-dimethylphenyl)-3-[3-[1- (2-methoxyethyl)indazol- 5-yl]-2-oxoimidazol-1-yl]-6,7-dihydro-4H- pyrazolo[4,3-c]pyridine- 5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-one SMD- TFA05-3 1.16 902([M+H]⁺) 102

3-[(1S,2S)-1-[5-(2-ethyl- 3-methylpyridin-4-yl)-2- [2-(4-fluoro-3,5-dimethylphenyl)-3-[3-[4- (1-hydroxy-2- methylpropan-2-yl)oxy-3-methoxyphenyl]-2- oxoimidazol-1-yl]-6,7- dihydro-4H-pyrazolo[4,3-c]pyridine-5- carbonyl]indol-1-yl]-2- methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one SMD- TFA05-3 1.17 922 ([M+H]⁺) 103

3-[(1S,2S)-1-[5-(2-ethyl- 3-methylpyridin-4-yl)-2- [2-(3-fluoro-5-methylphenyl)-3-(3- isoquinolin-6-yl-2- oxoimidazol-1-yl)-6,7-dihydro-4H-pyrazolo[4,3- c]pyridine-5- carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-one SMD- TFA05-3 0.96 841([M+H]⁺) 104

3-[(1S,2S)-1-[2-[2-(4- chloro-3,5- dimethylphenyl)-3-[3-(1-methylindazol-5-yl)-2- oxoimidazol-1-yl]-6,7- dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5- (2-ethyl-3-methylpyridin- 4-yl)indol-1-yl]-2-methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-one SMD- TFA05-3 1.20 875([M+H]⁺) 105

3-[(1S,2S)-1-[2-[3-[3- (1,3-dimethyl-2- oxoquinolin-6-yl)-2-oxoimidazol-1-yl]-2-(3- methylphenyl)-6,7- dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5- (2-ethyl-3-methylpyridin- 4-yl)indol-1-yl]-2-methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-one SMD- TFA05-3 1.16 867([M+H]⁺) 106

3-[(1S,2S)-1-[2-[2-(2,6- dimethylpyridin-4-yl)-3- [3-(1-methylindazol-5-yl)-2-oxoimidazol-1-yl]- 6,7-dihydro-4H- pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(2-ethyl-3- methylpyridin-4-yl)indol- 1-yl]-2-methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-one SMD- TFA05-3 0.86 841([M+H]⁺) 107

3-[(1S,2S)-1-[5-(2,3- dimethylpyridin-4-yl)-2- [2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(1- methyl-2-oxoquinolin-6-yl)-2-oxoimidazol-1-yl]- 6,7-dihydro-4H- pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2- methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-oneSMD- TFA05-3 1.09 871 ([M+H]⁺) 108

3-[(1S,2S)-1-[2-[2-(2- fluoro-3-methylphenyl)- 3-[3-[1-(2-methoxyethyl)indazol-5- yl]-2-oxoimidazol-1-yl]- 6,7-dihydro-4H-pyrazolo[4,3-c]pyridine- 5-carbonyl]-5-(2- methoxy-3-methylpyridin-4-y)indol- 1-yl]-2- methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one SMD- TFA05-3 1.38 890 ([M+H]⁺) 109

3-[(1S,2S)-1-[2-[2-(4- fluoro-3,5- dimethylphenyl)-3-[3-(4-fluoro-l-methylindazol- 5-yl)-2-oxoimidazol-1- yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine- 5-carbonyl]-5-(oxan-4- yl)indol-1-yl]-2-methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-one SMD- TFA05-1 1.34 841([M+H]⁺) 110

3-[(1S,2S)-1-[2-[2-(4- fluoro-3,5- dimethylphenyl)-3-[3-(1-methylindazol-5-yl)-2- oxoimidazol-1-yl]-6,7- dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5- (2-methylpyrazol-3- yl)indol-1-yl]-2-methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-one SMD- TFA05-3 1.30 820([M+H]⁺) 111

3-[(1S,2S)-1-[5-(3- chloro-2-methylpyridin- 4-yl)-242-(4-fluoro-3,5-dimethylphenyl)-3-[3-[1- (2-methoxyethyl)indazol- 5-yl]-2-oxoimidazol-1-yl]-6,7-dihydro-4H- pyrazolo[4,3-c]pyridine- 5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-one SMD- TFA05-3 1.24 908([M+H]⁺) 112

3-[(1S,2S)-1-[2-[2-(3,5- dimethylphenyl)-3-[3-(1- methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7- dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5- (2-ethylpyridin-4- yl)indol-1-yl]-2-methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-one SMD- FA05-3 0.95 826([M+H]⁺) 113

3-[(1S,2S)-1-[2-[2-(4- fluoro-3,5- dimethylphenyl)-3-[3-(1-methylindazol-5-yl)-2- oxoimidazol-1-yl]-6,7- dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5- (5-oxaspiro[3.5]nonan-8- yl)indol-1-yl]-2-methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-one SMD- TFA05-2 1.47 863([M+H]⁺) 114

3-[(1S,2S)-1-[2-[2-(3,5- dimethylphenyl)-3-[3- (oxan-4-yl)-2-oxoimidazol-1-yl]-6,7- dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5- (2-ethyl-3-methylpyridin- 4-yl)indol-1-yl]-2-methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-one SMD- TFA05-3 1.07 795([M+H]⁺) 115

3-[(1S,2S)-1-[2-[2-(3,5- dimethylphenyl)-6- methyl-3-[3-(1-methylidndazio-5-yl)-2- oxoimidazol-1-yl]6,7- dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5- (2-ethyl-3-methylpyridin- 4-yl)indol-1-yl]-2-methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-one SMD- TFA05-3 1.17 854([M+H]⁺) 116

3-[(1S,2S)-1-[2-[(4S)-2- (4-fluoro-3,5- dimethylphenyl)-4-methyl-3-[3-(1- methylindazol-5-yl)-2- oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3- c]pyridine-5-carbonyl]-5-(oxan-4-yl)indol-1-yl]-2- methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-oneSMD- TFA05-2 1.39 837 ([M+H]⁺) 117

3-[(1S,2S)-1-[2-[(4S)-2- (4-fluoro-3,5- dimethylphenyl)-3-[3-[1-(2-hydroxyethyl)indazol- 5-yl]-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro- 4H-pyrazolo[4,3- c]pyridine-5-carbonyl]-5-(oxan-4-yl)indol-1-yl]-2- methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-oneSMD- TFA05-1 1.27 867 ([M+H]⁺) 118

3-[(1S,2S)-1-[2-[(4S)-2- (4-fluoro-3,5- dimethylphenyl)-4-methyl-3-[3-[4-(oxan-4- yl)phenyl]-2- oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3- c]pyridine-5-carbonyl]-5-(oxan-4-y)indol-1-yl]-2- methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-oneSMD- TFA05-1 1.49 867 ([M+H]⁺) 119

3-[(1S,2S)-1-[2-[(4S)-3- 3-[1-[(3S)-1- acetylpyrrolidin-3-yl]indazol-5-yl]-2- oxoimidazol-1-yl]-2-(4- fluoro-3,5-dimethylphenyl)-4- methyl-6,7-dihydro-4H- pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4- yl)indol-1-yl]-2- methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one SMD- TFA05-1 1.29 934 ([M+H]⁺) 120

3-[(1S,2S)-1-[2-[(4S)-2- (4-fluoro-3,5- dimethylphenyl)-4-methyl-3-[3-[1-[2-[4- (oxetan-3-yl)piperazin-1-yl]ethyl]indazol-5-yl]-2- oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3- c]pyridine-5-carbonyl]-5-(oxan-4-y)indol-1-yl]-2- methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-oneSMD- TFA05-1 1.08 992 ([M+H]⁺) 121

3-[(1S,2S)-1-[2-[(4S)-2- (4-fluoro-3,5- dimethylphenyl)-4-methyl-3-[3-[3-methyl-4- [6-(4-methylpiperazin-1- yl)pyrimidin-4-yl]phenyl]-2- oxoimidazol-1-yl]-6,7- dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5- (oxan-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-one SMD- TFA05-1 0.96 973([M+H]⁺) 122

3-[(1S,2S)-1-[[2-[(4S)-2- (4-fluoro-3,5- dimethylphenyl)-4-methyl-3-[2-oxo-3-[1- (2,2,2- trifluoroethyl)indazol-5-yl]imidazol-1-yl]-6,7- dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5- (oxan-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-one SMD- TFA05-1 1.45 905([M+H]⁺) 123

3-[(1S,2S)-1-[2-[(4S)-2- (4-fluoro-3,5- dimethylphenyl)-4-methyl-3-[3-(3- methylimidazo[1,5- alpyridin-7-yl)-2-oxoimidazol-1-yl]-6,7- dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5- (oxan-4-y)indol-1-yl]-2-methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-one SMD- TFA05-1 1.07 837([M+H]⁺) 124

3-[(1S,2S)-1-[2-[(4S)-2- (4-fluoro-3,5- dimethylphenyl)-4-methyl-3-[3-(3- methylimidazo[1,5- a]pyridin-6-yl)-2-oxoimidazol-1-yl]-6,7- dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5- (oxan-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-one SMD- TFA05-1 1.07 837([M+H]⁺) 125

3-[(1S,2S)-1-[[2-[(4S)-3- [3-(1,4-dimethylindazol-5-yl)-2-oxoimidazol-1- yl]-1-2-(4-fluoro-3,5- dimethylphenyl)-4-methyl-6,7-dihydro-4H- pyrazolo[4,3-c]pyridine- 5-carbonyl]-5-(oxan-4-yl)indol-1-yl]-2- methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-one SMD-TFA05-1 1.37 851 ([M+H]⁺) 126

3-[(1S,2S)-1-[2-[(4S)-3- [3-[1-[2- (dimethylamino)ethyl]indazol-5-yl]-2- oxoimidazol-1-yl]-2-(4- fluoro-3,5- dimethylphenyl)-4-methyl-6,7-dihydro-4H- pyrazolo[4,3-c]pyridine- 5-carbonyl]-5-[(4S)-2,2-dimethyloxan-4-yl]indol- 1-yl]-2- methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one SMD- TFA05-1 1.15 922 ([M+H]⁺) 127

3-[(1S,2S)-1-[2-[(4S)-3- [3-(1,4-dimethylindazol- 5-yl)-2-oxoimidazol-1-yl]-2-(4-fluoro-3,5- dimethylphenyl)-4- methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine- 5-carbonyl]-5-[(4S)-2,2-dimethyloxan-4-yl]indol- 1-yl]-2- methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one SMD- TFA05-1 1.44 879 ([M+H]⁺) 128

3-[(1S,2S)-1-[5-(2,2- dimethylmorpholin-4-yl)- 2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4- fluoro-1-methylindazol- 5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro- 4H-pyrazolo[4,3- c]pyridine-5-carbonyl]indol-1-yl]-2- methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-oneSMD- TFA05-1 1.30 884 ([M+H]⁺) 129

3-[(1S,2S)-1-[6-fluoro-2- [(4S)-2-(4-fluoro-3,5- dimethylphenyl)-4-methyl-3-[3-(1- methylindazol-5-yl)-2- oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3- c]pyridine-5-carbonyl]-5-(oxan-4-yl)indol-1-yl]-2- methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-oneSMD- TFA05-1 1.38 855 ([M+H]⁺) 130

3-[(1S,2S)-1-[3-fluoro-2- [(4S)-2-(4-fluoro-3,5- dimethylphenyl)-4-methyl-3-[3-(1- methylindazol-5-yl)-2- oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3- c]pyridine-5-carbonyl]-5-(oxan-4-yl)indol-1-yl]-2- methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-oneSMD- TFA05-1 1.40 855 ([M+H]⁺) 131

3-[(1S,2S)-1-fluoro-2- [(4S)-2-(4-fluoro-3,5- dimethylphenyl)-4-methyl-3-[3-(1- methylindazol-5-yl)-2- oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3- c]pyridine-5-carbonyl]-5-(oxan-4-yl)indol-1-yl]-2- methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-oneSMD- TFA05-1 1.38 855 ([M+H]⁺) 132

3-[1-[2-[2-(4-fluoro-3,5- dimethylphenyl)-3-[3-[1-(2-methoxyethyl)indazol- 5-yl]-2-oxoimidazol-1- yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine- 5-carbonyl]-5-(oxan-4- yl)indol-1yl]cyclopropyl]-4H- 1,2,4-oxadiazol-5-one SMD- TFA05-2 1.28 853 ([M+H]⁺)133

3-[1-[2-[2-(4-fluoro-3,5- dimethylphenyl)-3-[3-(1-methylindazol-5-yl)-2- oxoimidazol-1-yl]-6,7- dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5- (oxan-4-yl)indol-1- yl]cyclopropyl]-4H-1,2,4-oxadiazol-5-one SMD- TFA05-2 1.26 809 ([M+H]⁺) 134

3-[[2-[2-(4-fluoro-3,5- dimethylphenyl)-3-[3-(1- methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7- dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5- (oxan-4-yl)indol-1- yl]methyl]-4H-1,2,4-oxadiazol-5-one SMD- TFA05-2 1.18 783 ([M+H]⁺) 135

3-[(1S,2S)-1-[2-[2-(4- fluoro-3,5- dimethylphenyl)-3-[3-(1-methylindazol-5-yl)-2- oxoimidazol-1-yl]-6,7- dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5- (oxan-4-yl)indol-1-yl]-2-(methoxymethyl)cyclopr opyl]-4H-1,2,4- oxadiazol-5-one SMD- TFA05-2 1.30853 ([M+H]⁺) 136

3-[(1S,2R)-1-[2-[2-(4- fluoro-3,5- dimethylphenyl)-3-[3-(1-methylindazol-5-yl)-2- oxoimidazol-1-yl]-6,7- dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5- (oxan-4-yl)indol-1-yl]-2- (morpholin-4-ylmethyl)cyclopropyl]- 4H-1,2,4-oxadiazol-5- one; formic acid SMD-TFA05-1 1.04 908 ([M+H]⁺) 137

3-[(2S,3R)-1-[2-[2-(4- fluoro-3,5- dimethylphenyl)-3-[3-(1-methylindazol-5-yl)-2- oxoimidazol-1-yl]-6,7- dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5- (oxan-4-yl]indol-1-yl]- 2,3-dimethylcyclopropyl]- 4H-1,2,4-oxadiazol-5-one SMD- TFA05-2 1.39 837([M+H]⁺) 138

3-[(1R,2S)-1-[2-[[2-(4- fluoro-3,5- dimethylphenyl)-3-[3-(1-methylindazol-5-yl)-2- oxoimidazol-1-yl]-6,7- dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]sulfonyl]- 5-(oxan-4-yl)indol-1-yl]-2-methylcyclopropyl]- 4H-1,2,4-oxadiazol-5-one SMD- TFA05-1 1.28 859([M+H]⁺) 139

3-[(1R)-1-[2-[2-(4- fluoro-3,5- dimethylphenyl)-3-[3-(1-methylindazol-5-yl)-2- oxoimidazol-1-yl]-6,7- dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5- (oxan-4-yl)indol-1- yl]ethyl]-4H-1,2,4-oxadiazol-5-one SMD- TFA05-2 1.28 797 ([M+H]⁺) 140

4-[2-[2-(3,5- dimethylphenyl)-3-[3-(1- methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7- dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5- (2-ethyl-3-methylpyridin-4-yl)indol-1-yl]-2,2- dimethylbutanoic acid SMD- FA05-3 0.90 816([M+H]⁺) 141

3-[2-[2-(3,5- dimethylphenyl)-3-[3-(1- methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7- dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5- (2-ethyl-3-methylpyridin-4-yl)indol-1-yl]propanoic acid SMD- TFA05-3 1.02 774 ([M+H]⁺) 142

2-[2-[2-(4-fluoro-3,5- dimethylphenyl)-3-[3-(1- methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7- dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5- (oxan-4-y)indol-1- yl]acetic acid SMD- TFA05-21.21 743 ([M+H]⁺) 143

(1S,2S)-1-[2-[2-(3,5- dimethylphenyl)-3-[3-(1- methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7- dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5- (2-ethyl-3-methylpyridin- 4-yl)indol-1-yl]-2-methylcyclopropane-1- carboxylic acid SMD- TFA05-3 1.08 800 ([M+H]⁺) 144

1-[2-(4-fluoro-3,5- dimethylphenyl)-5-[5- (oxan-4-yl)-1-(1H-1,2,4-triazol-5- ylmethyl)indole-2- carbonyl]-6,7-dihydro- 4H-pyrazolo[4,3-c]pyridin-3-yl]-3-(1- methylindazol-5- yl)imidazol-2-one SMD- TFA05-11.10 766 ([M+H]⁺) 145

1-[2-(4-fluoro-3,5- dimethylphenyl)-5-[1- [(1S,2S)-2-methyl-1-(5-sulfanylidene-4H-1,2,4- oxadiazol-3- yl)cyclopropyl]-5-(oxan-4-yl)indole-2-carbonyl]- 6,7-dihydro-4H- pyrazolo[4,3-c]pyridin-3-yl]-3-(1-methylindazol-5- yl)imidazol-2-one SMD- TFA05-2 1.45 839([M+H]⁺) 146

3-[(1S,2S)-1-[2-[2-(4- fluoro-3,5- dimethylphenyl)-3-[3-(1-methylindazol-5-yl)-2- oxoimidazol-1-yl]-6,7- dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5- (oxan-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H- 1,2,4-thiadiazol-5-one SMD- TFA05-2 1.46 839([M+H]⁺) 147

1-[2-(4-fluoro-3,5- dimethylphenyl)-5-[1- [(1S,2S)-2-methyl-1-(1H-tetrazol-5- yl)cyclopropyl]-5-(oxan- 4-yl)indole-2-carbonyl]-6,7-dihydro-4H- pyrazolo[4,3-c]pyridin-3- yl]-3-(1-methylindazol-5-yl)imidazol-2-one SMD- TFA05-2 1.26 807 ([M+H]⁺) 148

(1S,2S)-1-[2-[2-(4- fluoro-3,5- dimethylphenyl)-3-[3-(1-methylindazol-5-yl)-2- oxoimidazol-1-yl]-6,7- dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5- (oxan-4-y)indol-1-yl]-2- methyl-N-methylsulfonylcycloprop ane-1-carboxamide SMD- TFA05-1 1.31 860 ([M+H]⁺)149

3-[(1S,2S)-1-[2-[[(4S)-2- (4-fluoro-3,5- dimethylphenyl)-4-methyl-3-[3-(1- methylindazol-5-yl)-2- oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3- c]pyridin-5-yl]methyl]-5-(oxan-4-yl)indol-1-yl]-2- methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-oneSMD- TFA05-2 1.17 823 ([M+H]⁺) 150

2-[2-[3-[3- (cyclohexylmethyl)-2- oxoimidazolidin-1yl]-2-phenyl-6,7-dihydro-4H- pyrazolo[4,3-c]pyridine- 5-carbonyl]-5-(2,3-dimethylpyridin-4- yl)indol-yl]-2- methylpropanoic acid SMD- TFA05-31.13 714 ([M+H]⁺) 151

3-[2-[2-[3-[3- (cyclohexylmethyl)-2- oxoimidazolidin-1-yl]-2-phenyl-6,7-dihydro-4H- pyrazolo[4,3-c]pyridine- 5-carbonyl]-5-(2,3-dimethylpyridin-4- yl)indol-1-yl]propan-2- yl]-4H-1,2,4-oxadiazol-5- oneSMD- TFA05-3 1.10 755 ([M+H]⁺) 152

3-[(1S,2S)-1-[2-[3-[3- (2,2-dimethylpropyl)-2- oxoimidazolidin-1-yl]-2-phenyl-6,7-dihydro-4H- pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(2-ethyl-3- methylpyridin-4-yl)indol- 1-yl]-2-methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-one SMD- TFA05-3 1.11 754([M+H]⁺) 153

3-[(1S,2S)-1-[5-(2-ethyl- 3-methylpyridin-4-yl)-2- [2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(1- methylindazol-5-yl)-2- oxoimidazolidin-1-yl]-6,7-dihydro-4H- pyrazolo[4,3-c]pyridine- 5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-one SMD- TFA05-3 1.15 860([M+H]⁺) 154

3-[(1S,2S)-1-[2-[2-(3,5- dimethylphenyl)-3-[3-(4-imidazol-1-ylphenyl)-2- oxoimidazolidin-1-yl]- 6,7-dihydro-4H-pyrazolo[4,3-c]pyridine- 5-carbonyl]-5-(2-ethyl-3-methylpyridin-4-yl)indol- 1-yl]-2- methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one SMD- TFA05-1 0.86 854 ([M+H]⁺) 155

3-[(1S,2S)-1-[2-[2-(3,5- dimethylphenyl)-3-[3-(1- methylindazol-5-yl)-2-oxoimidazolidin-1-yl]- 6,7-dihydro-4H- pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(2-ethyl-3- methylpyridin-4-yl)indol- 1-yl]-2-methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-one SMD- TFA05-3 1.14 842([M+H]⁺) 156

3-[(1S,2S)-1-[2-[2-(3,5- dimethylphenyl)-3-(5- imidazol-1-yl-3-oxo-1H-isoindol-2-yl)-6,7- dihydro-4H-pyrazolo[4,3- c]pyridine-5-carbonyl]-5-(2-ethyl-3-methylpyridin- 4-yl)indol-1-yl]-2- methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one SMD- FA05-3 0.79 825 ([M+H]⁺) 157

3-[(1S,2S)-1-[2-[2-(3,5- dimethylphenyl)-3-[N,3- dimethyl-4-(3-propan-2-yl-1,2,4-triazol-4- yl)anilino]-6,7-dihydro- 4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5- (2-ethyl-3-methylpyridin- 4-yl)indol-1-yl]-2-methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-one SMD- TFA05-3 1.10 856([M+H]⁺) 158

3-[(1S,2S)-1-[5-(2-ethyl- 3-methylpyridin-4-yl)-2- [2-(4-fluoro-3,5-dimethylphenyl)-3-[N- methyl-4-(2-propan-2- ylimidazol-1-yl)anilino]-6,7-dihydro-4H- pyrazolo[4,3-c]pyridine- 5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-one SMD- TFA05-3 1.05 859([M+H]⁺) 159

3-[(1S,2S)-1-[5-(2-ethyl- 3-methylpyridin-4-yl)-2- [2-(4-fluoro-3,5-dimethylphenyl)-3-[4-(3- propan-2-yl-1,2,4-triazol-4-yl)anilino]-6,7-dihydro- 4H-pyrazolo[4,3- c]pyridine-5-carbonyl]indol-1-yl]-2- methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-oneSMD- FA05-3 0.91 846 ([M+H]⁺)

<Example 60> Preparation of Monosodium Salt Hydrate Crystal of Compound1

Acetonitrile (3.02 mL) was added to3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one(Compound 1, 1005.5 mg) obtained in Example 1 to dissolve the compoundat room temperature. 5M Sodium hydroxide aqueous solution (0.495 mL) andseed crystals of sodium salt hydrate of Compound 1 were added to thesolution, and the mixture was stirred at room temperature for 2 h.Tert-Butylmethyl ether (3.02 mL) was also added, and the mixture wasstirred at room temperature for 1 h., and then tert-butylmethyl ether(9.05 mL) was added and the mixture was stirred at room temperature for2 h. to obtain sodium salt hydrate crystals of the titled compound(1007.0 mg) as powder crystals (Sample 160a). Note that seed crystalswere obtained by the following method.

DMSO (0.244 mL) and 2M sodium hydroxide aqueous solution (0.032 mL) wereadded to Compound 1 (26.9 mg). This solution (0.030 mL) was freeze-driedat −20° C. for 2 days. Acetonitrile (0.015 mL) was added to theobtained, freeze-dried product, and the mixture was stirred by shakingat room temperature for 2 days, and then tert-butylmethyl ether (0.015mL) was added, and the mixture was stirred by shaking at toomtemperature for 12 days to obtain sodium salt hydrate crystals ofCompound 1 as powder crystals (Sample 160b).

<Example 161> Preparation of Crystal of Example Compound 66

3-[(1S,2S)-1-[5-[(4S)-2,2-Dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-[3-(1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one(Example Compound 66, 400.3 mg) was suspended in ethanol (8.00 mL), towhich seed crystals of Example Compound 66 were added, and the mixturewas stirred at 70° C. for 5 min. After the suspension was stirred at 50°C. for 1 h., it was stirred at room temperature for 17 h. to obtaincrystals (381.1 mg) of Example Compound 66 as powder crystals (Sample161a). Note that seed crystals were obtained by the following method.

Example Compound 66 (31.8 mg) was suspended in ethanol (0.636 mL), andstirred at 80° C. After the suspension was stirred at 40° C. for 1 h.,it was stirred at room temperature for 22 h. to obtain crystals (24.2mg) of Example Compound 66 as powder crystals (Sample 161b).

<Example 162> Preparation of Hemicalcium Salt Hydrate Crystal of ExampleCompound 67

Ethanol (5.60 mL) and 2M sodium hydroxide aqueous solution (0.75 mL)were added to3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one(Example Compound 67, 1120 mg) and the compound was dissolved at roomtemperature. 1.26 M calcium acetate aqueous solution (0.68 mL), seedcrystals of the calcium salt hydrate of Example Compound 67 and water(0.68 mL) were added to the solution, and the mixture was stirred atroom temperature for 3 h. Further, water (1.2 mL) was added and themixture was stirred at room temperature for 1 h., and then water (2.3mL) was added and the mixture was stirred at room temperature for 1 h.to obtain calcium salt hydrate crystals (973.0 mg) of Example Compound67 as powder crystals (Sample 162a). Note that seed crystals wereobtained by the following method.

Example Compound 67 (69.0 mg) was dissolved in DMSO (0.229 mL), and1.06M calcium methoxyethoxide (0.147 mL) was added. This solution (0.015mL) was freeze-dried at −20° C. for 2 days. Water-acetonitrile mixture(3:1, 0.015 mL) was added to the obtained, freeze-dried product, and themixture was stirred by shaking at room temperature for 7 days to obtaincalcium salt hydrate crystals of Example Compound 67 as powder crystals(Sample 162b).

<Example 163> Powder X-Ray Diffractometry

The sodium salt hydrate crystals (Samples 160a and 160b) of Compound 1obtained in Example 160, the crystals (Samples 161a and 161b) of ExampleCompound 66 obtained in Example 161, the calcium salt hydrate crystals(Samples 162a and 162b) of Example Compound 67 obtained in Example 162were each subjected to powder X-ray diffractometry by the followingmeasurement method. The results are shown in FIG. 1 to FIG. 6 .

Measurement Device: D8 Discover with GADDS CS diffractometer (BrukerAXS)

Anode: Cu

Voltage: 40 kV

Current: 40 mA

Scan Range: 5-25.3°

Step Width: 0.02°

<Example 164> Thermogravimetry/Differential Thermal Analysis

The sodium salt hydrate crystal of Compound 1 (Sample 160a) and thecalcium salt hydrate crystal of Example Compound 67 (Sample 162a) wereeach subjected to thermogravimetry/differential thermal analysis by thefollowing measurement method. The results are shown in FIG. 7 and FIG. 8. Note that Sample 160a was dehydrated by approximately 110° C. andshowed no clear melting point. Also, Sample 162a was dehydrated byapproximately 240° C. and showed no clear melting point.

Measurement Device: EXSTAR TG/DTA6200R (Seiko Instruments Inc. (CurrentCompany Name: Hitachi High-Tech Science Corporation))

Measurement Range: 30-350° C.

Heat rate: 10° C./min.

Atmosphere: Nitrogen

<Example 165> Karl Fischer Water Measurement

The rate of water content in the sodium salt hydrate crystal of Compound1 (Sample 160a) and the calcium salt hydrate crystal (Sample 162a) ofExample Compound 67 were measured using the coulometric Karl Fischermoisture meter (Metrohm, 756 KF Coulometer). The result was 7.4% forSample 160a and 6.2% for Sample 162a.

From the results of Example 164 and Example 165, it was confirmed thatthe waters contained in the sodium salt hydrate crystal of Compound 1and the calcium salt hydrate crystal of Example Compound 67 were mainlycrystalline water.

<Test Example 1> Measurement of in vitro cAMP Signal Activation of aCompound in Human GLP1R

<Peptide>

The human GLP-1 (7-37) was obtained from PEPTIDE INSTITUTE, INC., and itwas dissolved in phosphate buffered saline to 200 μM, then stored in afreezer of −80° C.

<Cell Culture>

A human GLP1R stably-expressing cell line (hGLP1R-HEK293) was used inthe experiment. The cells were cultured in a Dulbecco's modified Eagle'smedium (DMEM) containing 10% fetal bovine serum (Sigma-Aldrich), 100units/mL penicillin G and 100 μg mL streptomycin sulfate (Gibco), and500 μg/mL Geneticin (Gibco), under a moist atmosphere containing 5% CO₂,at 37° C.

<cAMP Assay>

hGLP1R-HEK293 was seeded in 96 well plates at 2.0×10⁴ cells per well andcultured over night. The medium for culturing the cells was changed to50 μL of Medium A (DMEM, 20 mM HEPES, 0.05% BSA, 0.5 mM3-isobutyl-1-methylxanthine) the next day, and the cells were incubatedat 37° C. for 30 min. Then, 50 μL of Medium B (DMEM, 20 mM HEPES, 0.05%BSA, 0.5 mM 3-isobutyl-1-methylxanthine) containing GLP-1 or thecompound was added, and the cells were incubated at 37° C. for anadditional 30 min. Then, 100 μL of Assay lysis buffer (AppliedBioscience) was added, and the cells were incubated at 37° C. for 30min. The cAMP concentration was quantified using cAMP HiRange kit(Cisbio Bioassays).

<Calculation of EC₅₀>

By setting the cAMP concentration when the human GLP-1 (7-37) was putinto action at a concentration of 1 nM to 10000, the cAMP concentrationof each well was converted to a reaction rate (0%). By using a 4parameter logistic regression analysis by XLfit (ver 5.4.0.8),dose-response curves of the each Example Compound were created, and thehalf maximal (500%) effective concentrations (EC₅₀) were calculated. Theresults are shown in Table 3.

TABLE 3 EC₅₀ of each Example Compound Example EC50 No. (nM)  1 8.8  25.6  3 6.1  4 12  5 6.1  6 2.9  7 3.2  8 2.5  9 1.8 10 2.8 11 1.1 12 2.713 3.7 14 2.3 15 2.2 16 0.51 17 1.0 18 1.3 19 1.3 20 1.9 21 1.6 22 2.323 1.8 24 2.5 25 4.0 26 0.77 27 2.3 28 1.9 29 1.4 30 1.4 31 0.74 32 0.9433 1.6 34 3.0 35 3.2 36 2.1 37 2.5 38 1.7 39 1.0 40 2.2 41 2.4 42 1.9 431.5 44 1.5 45 1.6 46 3.3 47 2.0 48 3.0 49 3.8 50 2.9 51 8.7 52 6.7 532.9 54 3.9 55 3.7 56 3.4 57 8.1 58 7.6 59 1.5 60 4.9 61 1.6 62 1.1 631.1 64 2.0 65 3.5 66 0.81 67 1.2 68 1.8 69 2.8 70 1.5 71 1.3 72 2.3 732.5 74 6.2 75 6.2 76 2.4 77 1.4 78 3.6 79 2.4 80 2.4

<Test Example 2>: Insulin Secretion Promoting and Blood Glucose LoweringEffects

A solution of Example Compound 67 (solvent composition: PEG400 (10 vol%): propylene glycol (10 vol %): 100 mM Glycine-NaOH buffer, pH 9.0 (80vol %)) was intravenously administered to a male cynomolgus monkey underanesthesia, for 40 min. continuously, and a steady-state drugconcentration in plasma of 0.94, 1.6 or 4.8 nmol/L was achieved.Likewise, a solution of exenatide (solvent: Tween 0.05%/PBS(−)), whichis a control drug, was administered in the same manner, and asteady-state drug concentration in plasma of 9.2 or 23.9 pmol/L wasachieved. To the vehicle control group, the solvent of Example Compound67 was administered. Next, a 50% glucose solution (glucoseadministration weight to the monkey: 0.5 g/kg) was intravenouslyadministered and a blood sample was collected every 5 min or 10 min tomeasure the plasma insulin and glucose concentrations. The area underthe curve was calculated from the time course of each parameter afterthe drug administration to evaluate the insulin secretion promotingeffect and the blood glucose lowering effect.

In the Example Compound 67 administered group, an increase in the areaunder the curve of insulin (FIG. 9 ) and a decrease in the area underthe curve of plasma glucose (FIG. 10) in a dose-dependent manner, wereobserved at a steady-state concentration in plasma of 0.94 to 4.8nmol/L. A similar increase in the area under the curve of insulin (FIG.9 ) and decrease in the area under the curve of plasma glucose (FIG. 10) were observed in exenatide (control drug) administered group at asteady-state plasma concentration of 9.2 to 23.9 pmol/L by thecontinuous intravenous administrations

Note that the 9.2 pmol/L (38.5 pg/mL) of exenatide was close to thelower limit of the therapeutic concentration range (50-350 pg/mL) ofexenatide in human diabetes patients (Drug interview form, Byettahypodermic injection 5 μg Pen 300, Byetta hypodermic injection 10 μg Pen300, September 2016 (revised ver. 9)). This result indicates thatExample Compound 67 exhibits an insulin secretion promoting effect and ablood glucose lowering effect that are equivalent to exenatide, at aplasma concentration of 1.6 nmol/L or higher.

<Test Example 3>: Anorexigenic Effects

Example Compound 67 was orally administered to male cynomolgus monkeys,for 5 consecutive days, and its effects on the food intake for 90 min.from 3 h. after administration were evaluated everyday. Likewise,exenatide, which is a control drug, was subcutaneously administered for5 consecutive days, and its effect on the food intake for 90 min. from30 min. after administration were evaluated. To the vehicle controlgroup, both a solvent for oral administration of Example Compound 67(DMSO (10 vol %): Cremophor EL (10 vol %): PEG 400 (15 vol %): 100 mMGlycine-NaOH buffer, pH 10 (65 vol %), 1 mL/kg) and a solvent forsubcutaneous administration of exenatide (0.05 w/v % Tween/PBS(−), 0.1mL/kg) were administered. At the same time, the solvent for subcutaneousadministration was additionally administered to the Example Compound 67administered group (concentration of administered drug, 0.05 or 0.1mg/mL), and the solvent for oral administration was additionallyadministered to the exenatide administered group (concentration ofadministered drug, 3 or 6 μg/mL).

Example Compound 67 suppressed the food intake in a dosage dependentmanner (FIG. 11A). The degree of suppression was almost equivalent tothe control drug exenatide (FIG. 11B). The plasma concentration of drug(mean value±standard error) immediately after measuring the food intakein each group were 8.0±1.0 nM (0.05 mg/kg group) and 16.3±2.3 nM (0.1mg/kg group) for the Example Compound 67 administered group and 91±8.5pM (0.3 μg/kg group) and 199±13.1 pM (0.6 μg/kg group) for the exenatideadministered group.

<Test Example 4> Pharmacokinetics of the Compounds

After oral administration (gavage administration using a gastriccatheter) of a calcium salt hydrate crystal (Sample 162a) suspension(Dosage: 0.05, 0.15, 0.45 and 1.35 mg/kg) prepared from Example Compound67 obtained in Example 162 to a male cynomolgus monkey (n=2 for eachdosage), blood was sequentially collected from the vein to obtainplasma. The plasma concentrations of the drug were determined by liquidchromatography tandem-mass spectrometry. The lower limit ofquantification was 0.3 ng/mL. The time profile of the plasmaconcentrations for the drug are shown in FIG. 12 and the time to reachthe maximum plasma concentration of the drug (T_(max)), the maximumplasma concentration of the drug (C_(max)) and the area under the plasmaconcentration—time curve of the drug up to 24 h. after administration(AUC_(0-24h)) are shown in Table 4.

In all dosages, the plasma concentrations of the drug reached C_(max) at2 h after oral administration, and then decreased in a similar timeprofile pattern. The increase in the plasma exposure of drug at dosagesof 0.05, 0.15, 0.45 and 1.35 mg/kg (Dosage ratio: 1:3:9:27) was nearlyproportional to the increase in the dosage (C_(max) ratio:1.0:4.3:6.7:31, AUC_(0-24h) ratio: 1.0:5.7:8.8:44). It was shown thatthe present substance was dose-proportionally absorbed in the intestinaltract and eliminated.

TABLE 4 The T_(max), C_(max), and AUC_(0-24 h) after oral administrationof the present substance to male cynomolgus monkeys Dose T_(max) C_(max)AUC_(0-24 h) (mg/kg) (Ratio) (h) (ng/mL) (Ratio) (ng · h/mL) (Ratio)0.05 1.0 2.0 4.78 1.0 23.7 1.0 0.15 3.0 2.0 20.7 4.3 135 5.7 0.45 9.02.0 32.0 6.7 208 8.8 1.35 27 2.0 148 31 1040 44

1. A compound represented by Formula (I):

wherein, X is —N═ or —CR^(a)═; R^(a) is selected from a hydrogen atom, ahalogen atom, and C₁₋₆ alkyl; Y is selected from —C(═O)—, —CHR—, and—S(═O)₂—; R is a hydrogen atom or C₁₋₆ alkyl; Q¹ is C₆₋₁₀ aryl or 5 to10 membered heteroaryl, wherein C₆₋₁₀ aryl and 5 to 10 memberedheteroaryl are optionally substituted with one to five substituentsindependently selected from a halogen atom, C₁₋₆ alkyl (wherein C₁₋₆alkyl is optionally substituted with one or more halogen atoms), andC₁₋₆ alkoxy; Q² is 3 to 12 membered heterocyclyl or 5 to 10 memberedheteroaryl, wherein 3 to 12 membered heterocyclyl and 5 to 10 memberedheteroaryl are optionally substituted with one to three substituentsindependently selected from a halogen atom, C₁₋₆ alkyl (wherein C₁₋₆alkyl is optionally substituted with one or more halogen atoms), C₁₋₆alkoxy, and —NR^(Qa)R^(Qb), and two C₁₋₆ alkyl groups together with acarbon atom to which they are attached may form C₃₋₈ carbocyclic ring;and R^(Qa) and R^(Qb) are independently selected from a hydrogen atom,C₁₋₆ alkyl, and (C₁₋₆ alkyl)carbonyl; R¹, R² and R³ are eachindependently selected from a hydrogen atom and C₁₋₆ alkyl (wherein,C₁₋₆ alkyl is optionally substituted with one or more substituentsindependently selected from a halogen atom, C₁₋₆ alkoxy, and hydroxy);R⁴, R⁵ and R⁶ are independently selected from a hydrogen atom, a halogenatom, and C₁₋₆ alkyl; R⁷ and R⁸ are independently a hydrogen atom orC₁₋₆ alkyl, wherein C₁₋₆ alkyl is optionally substituted with one ormore substituents independently selected from a halogen atom and C₃₋₁₅cycloalkyl, or R⁷ and R⁸ together with a carbon atom to which they areattached may form C₃₋₁₅ cycloalkane ring, wherein C₃₋₁₅ cycloalkane ringformed by R⁷ and R⁸ together is optionally substituted with one to threeC₁₋₆ alkyl, wherein C₁₋₆ alkyl is optionally substituted with one ormore substituents independently selected from a halogen atom, hydroxy,—NR^(7a)R^(7b), C₁₋₆ alkoxy, and 3 to 12 membered heterocyclyl, andR^(7a) and R^(7b) are independently selected from a hydrogen atom, C₁₋₆alkyl, and (C₁₋₆ alkyl)carbonyl; n1 is an integer of 0 to 3; n2 is aninteger of 0 to 5; R⁹ is selected from a group represented by Formula(IIa), (IIb), (IIc), (IId):

—CO₂R^(9f), and —C(═O)—NR^(9g)R^(9h); and R^(9a), R^(9b), R^(9c),R^(9d), and R^(9g) are each independently selected from a hydrogen atom,C₁₋₆ alkyl (wherein C₁₋₆ alkyl is optionally substituted with one ormore substituents independently selected from a halogen atom and C₁₋₆alkoxy), and (C₁₋₆ alkyl)carbonyl; R^(9e) is a hydrogen atom, or C₁₋₆alkyl that is optionally substituted with one or more halogen atoms;R^(9f) is a hydrogen atom or C₁₋₆ alkyl; R^(9h) is a hydrogen atom, C₁₋₆alkyl, (C₁₋₆ alkyl)carbonyl, cyano, or —S(═O)_(n3)—R^(9i); n3 is aninteger of 0 to 2; and R⁹ is C₁₋₆ alkyl; Z¹ is selected from a grouprepresented by Formula (IIIa), (IIIb), (IIIc), (IIId), and (IIIe):

wherein R^(za) is selected from a hydrogen atom, C₁₋₆ alkyl, and (C₁₋₆alkyl)carbonyl; R^(zb) and R^(zc) are independently a hydrogen atom orC₁₋₆ alkyl; n4 is an integer of 1 to 3; n5 and n6 are independently aninteger of 0 to 10 (* represents a binding position with apyrazolopyridine structure, and ** represents a binding position withZ²); Z² is selected from C₁₋₆ alkyl, C₃₋₁₅ cycloalkyl, 3 to 12 memberedheterocyclyl, C₆₋₁₀ aryl and 5 to 10 membered heteroaryl, wherein C₃₋₁₅cycloalkyl, 3 to 12 membered heterocyclyl, C₆₋₁₀ aryl, and 5 to 10membered heteroaryl are optionally substituted with one to fivesubstituents independently selected from Group A: Group A: a) oxo, b) ahalogen atom, c) cyano, d) —NR^(zd)R^(ze); wherein R^(zd) and R^(ze) areindependently selected from a hydrogen atom, C₁₋₆ alkyl and (C₁₋₆alkyl)carbonyl, wherein C₁₋₆ alkyl is optionally substituted with one ormore substituents independently selected from hydroxy, a halogen atomand C₁₋₆ alkoxy, e) —C(═O)—NR^(zf)R^(zg); wherein R^(zf) and R^(zg) areindependently selected from a hydrogen atom, C₁₋₆ alkyl and (C₁₋₆alkyl)carbonyl, wherein C₁₋₆ alkyl is optionally substituted with one ormore substituents independently selected from hydroxy, a halogen atomand C₁₋₆ alkoxy, f) —S(═O)_(n7)—R^(zh); wherein n7 is an integer of 0 to2; and R^(zh) is a hydrogen atom or C₁₋₆ alkyl, g) C₁₋₆ alkyl; whereinC₁₋₆ alkyl is optionally substituted with one or more substituentindependently selected from a halogen atom, hydroxy, —NR^(zi)R^(zj),C₁₋₆ alkoxy, and 3 to 12 membered heterocyclyl, wherein R^(zi) andR^(zj) are independently a hydrogen atom or C₁₋₆ alkyl, and wherein 3 to12 membered heterocyclyl is optionally substituted with one or moresubstituents independently selected from hydroxy, C₁₋₆ alkyl and 3 to 12membered heterocyclyl, h) C₁₋₆ alkoxy; wherein C₁₋₆ alkoxy is optionallysubstituted with one or more substituent independently selected fromhydroxy, a halogen atom, and C₁₋₆ alkoxy, i) 3 to 12 memberedheterocyclyl; wherein 3 to 12 membered heterocyclyl is optionallysubstituted with one or more substituents independently selected fromC₁₋₆ alkyl and (C₁₋₆ alkyl)carbonyl, j) C₆₋₁₀ aryl; wherein C₆₋₁₀ arylis optionally substituted with one or more (C₁₋₆ alkyl)carbonyl, and k)5 to 10 membered heteroaryl; wherein 5 to 10 membered heteroaryl isoptionally substituted with one or more substituents independentlyselected from C₁₋₆ alkyl, C₁₋₆ alkoxy, —NR^(zk)R^(zl), and 3 to 12membered heterocyclyl, wherein R^(zk) and R^(zl) are independentlyselected from a hydrogen atom, C₁₋₆ alkyl and (C₁₋₆ alkyl)carbonyl, andwherein 3 to 12 membered heterocyclyl is optionally substituted with oneor more substituents independently selected from C₁₋₆ alkyl and (C₁₋₆alkyl)carbonyl; a salt thereof, or a solvate of either the compound or asalt of the compound.
 2. The compound according to claim 1, a saltthereof, or a solvate of either the compound or a salt of the compound,wherein Q¹ is phenyl or pyridyl, and phenyl or pyridyl is substitutedwith one to four substituents independently selected from a halogen atomand C₁₋₆ alkyl.
 3. The compound according to claim 1 or 2, a saltthereof, or a solvate of either the compound or a salt of the compound,wherein R⁷ and R⁸ are both a hydrogen atom; R⁷ and R⁸ are both C₁₋₆alkyl; R⁷ is a hydrogen atom and R⁸ is C₁₋₆ alkyl; or R⁷ and R⁸ togetherwith a carbon atom to which they are attached form C₃₋₈ cycloalkanering, wherein C₃₋₈ cycloalkyl formed is optionally substituted with oneto two C₁₋₆ alkyl, and C₁₋₆ alkyl is optionally substituted with one ormore substituents independently selected from hydroxy, C₁₋₆ alkoxy, and3 to 12 membered heterocyclyl.
 4. The compound according to any one ofclaims 1 to 3, a salt thereof, or a solvate of either the compound or asalt of the compound, wherein Z² is selected from C₁₋₆ alkyl, C₃₋₁₅cycloalkyl, 3 to 12 membered heterocyclyl, C₆₋₁₀ aryl, and 5 to 10membered heteroaryl, wherein C₃₋₁₅ cycloalkyl, 3 to 12 memberedheterocyclyl, C₆₋₁₀ aryl, and 5 to 10 membered heteroaryl are optionallysubstituted with one to four substituents independently selected fromGroup B: Group B: a) oxo, b) a halogen atom, c) —NR^(zd1)R^(ze1);wherein R^(zd1) and R^(ze1) are independently selected from a hydrogenatom, C₁₋₆ alkyl and (C₁₋₆ alkyl)carbonyl, and C₁₋₆ alkyl is optionallysubstituted with one or more C₁₋₆ alkoxy, d) —S(═O)_(n7)—R^(zh1);wherein n7 is an integer of 0 to 2, R^(zh1) is C₁₋₆ alkyl, e) C₁₋₆alkyl; wherein C₁₋₆ alkyl is optionally substituted with one or moresubstituents independently selected from a halogen atom, hydroxy,—NR^(zi)R^(zj), C₁₋₆ alkoxy, and 3 to 12 membered heterocyclyl, whereinR^(zi) and R^(zj) are independently a hydrogen atom or C₁₋₆ alkyl, andwherein 3 to 12 membered heterocyclyl is optionally substituted with oneor more substituents independently selected from hydroxy, C₁₋₆ alkyl and3 to 12 membered heterocyclyl, f) C₁₋₆ alkoxy; wherein C₁₋₆ alkoxy isoptionally substituted with one or more hydroxy, g) 3 to 12 memberedheterocyclyl; wherein 3 to 12 membered heterocyclyl is optionallysubstituted with one or more (C₁₋₆ alkyl)carbonyl, h) 5 to 10 memberedheteroaryl; wherein 5 to 10 membered heteroaryl is optionallysubstituted with one or more substituents independently selected fromC₁₋₆ alkyl, and —NR^(zk1)R^(zl1); and R^(zk1) and R^(zl1) areindependently selected from a hydrogen atom and C₁₋₆ alkyl.
 5. Thecompound according to any one of claims 1 to 4, a salt thereof, or asolvate of either the compound or a salt of the compound, wherein Y is—C(═O)—.
 6. The compound according to any one of claims 1 to 5, a saltthereof, or a solvate of either the compound or a salt of the compound,wherein R¹ is a hydrogen atom.
 7. The compound according to any one ofclaims 1 to 6, a salt thereof, or a solvate of either the compound or asalt of the compound, wherein n1 and n2 are both
 0. 8. The compoundaccording to any one of claims 1 to 7, a salt thereof, or a solvate ofeither the compound or a salt of the compound, wherein R⁹ is representedby Formula (IIb):


9. The compound according to any one of claims 1 to 8, a salt thereof,or a solvate of either the compound or a salt of the compound, wherein Xis —N═, —CH═, or —CF═.
 10. The compound according to any one of claims 1to 9, a salt thereof, or a solvate of either the compound or a salt ofthe compound, wherein Z¹ is represented by Formula (IIIa):

wherein * represents a binding position with a pyrazolopyridinestructure, and ** represents a binding position with Z².
 11. Apharmaceutical composition comprising the compound according to any oneof claims 1 to 10, a salt thereof, or a solvate of either the compoundor a salt of the compound as an active ingredient.
 12. A preventiveagent or a therapeutic agent for non-insulin-dependent diabetes mellitus(Type 2 diabetes), hyperglycemia, impaired glucose tolerance, insulindependent diabetes mellitus (Type 1 diabetes), diabetic complication,obesity, hypertension, hyperlipidemia, arteriosclerosis, coronary heartdisease, brain infarction, non-alcoholic steatohepatitis, Parkinson'sdisease, or dementia, wherein the preventative agent or the therapeuticagent comprises the compound according to any one of claims 1 to 10, asalt thereof, or a solvate of either the compound or a salt of thecompound as an active ingredient.
 13. A preventive agent or atherapeutic agent for non-insulin-dependent diabetes mellitus (Type 2diabetes) or obesity comprising the compound according to any one ofclaims 1 to 10, a salt thereof, or a solvate of either the compound or asalt of the compound as an active ingredient.